Biological Components of Substance Abuse and Addiction

September 1993 OTA-BP-BBS-117 NTIS order #PB94-134624 GPO stock #052-003-01350-9 Recommended Citation: U.S. Congress, Mice of Technology Assessment, BioZogicaZ Components of Substance Abuse and Addiction, OTA-BP-BBS-1 17 (Washington, DC: U.S. Government printing Offke, September 1993).

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ubstance abuse and addiction are complex phenomena that defy simple explanation or description. A tangled interaction of factors contributes to an individual’s experimentation with, use, and perhaps subsequent abuse of drugs. Regardless of the mix of contributing factors, the actions and effectss exerted by drugs of abuse underlie all substance abuse and addiction. In order to understand substance abuse and addiction it is first necessary to understand how drugs work in the brain, why certain drugs have the potential for being abused, and what, if any, biological differences exist among individuals in their susceptibility to abuse drugs. This background paper is the first of two documents being produced by OTA as part of an assessment of Technologies for Understanding the Root Causes of Substance Abuse and Addiction. The assessment was requested by the House Committee on Government Operations, the Senate Committee on Governmental Affairs, and the Senate Committee on Labor and Human Resources. This background paper describes biological contributing factors to substance abuse and addiction. The second document being produced by this study will discuss the complex interactions of biochemical, physiological, psychological, and sociological factors leading to substance abuse and addiction. OTA gratefully acknowledges the generous help of the Advisory Panel, contributors, and reviewers who gave their time to this project. OTA, however, remains solely responsible for the contents of this background paper. a“+- - Roger C. Herdman, Director

iii Advisory Panel

Patricia Evans Sheppard Kellam David F. Musto Chair School of Hygiene and Child Studies Center Bayview-Hunter’s Point Public Health Yale University Foundation The Johns Hopkins University New Haven, CT San Francisco, CA Baltimore, MD Ruben Ortega Marilyn Agulrre-Mollna Herbert Kleber Ruben Ortega Associates Robert Wood Johnson Medical College of Physicians and Phoenix, AZ School surgeons Piscataway, NJ Columbia University Sue Rusche New York NY National Families in Action Jeffrey G. Becker Atlanta, GA The Beer Institute George Koob Washington, DC Department of Neuropharmacology Lawrence Wallack The Scripps Research Institute School of Public Health Lawrence S. Brown, Jr. La Jolla, CA University of California Berkeley Addiction Research and Berkeley, CA Treatment Corp. Mary Jeanne Kreek Brooklyn, NY Department of Biology and Kenneth E. Warner Addictive Diseases School of Public Health Mary Edwards The Rockefeller University University of Michigan Camden House New York, NY Ann Arbor, MI Detroit, Ml John Lucas Roger W. Wilkins Bernard Ellis, Jr. John Lucas Enterprises Robinson Professor of History and New Mexico Department of Houston, TX American Culture Health George Mason University Santa Fe, NM Spero Manson Fairfax, VA University Health Science Center Robbie M. Jackman Colorado Psychiatric Hospital State of Tennessee Denver, CO Department of Public Health Nashville, TN Roger Meyer Department of Psychiatry University of Connecticut Farmington, CT

NOTE: OTA apprecutes and is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel members. The panel does not, however, necessarily approve, “disapprove, or endorse this report. OTA assumes full responsibility for the report and the accuracy of its contents.

iv Preject Staff

Clyde Behney Kevin W. O’Connor ADMINISTRATIVE STAFF Assistant Director Project Director Cecile Parker Health, Life Sciences Jennifer Schmidt Office Administrator and the Environment Analyst Linda Rayford-Journiette Michael Gough Thomas R. Vischi PC! Specialist Program Manager OTA Fellow Jene Lewis Biological and Behavioral Sciences Ellen McDermott Administrative Secretary Program Research Assistant

PRIMARY CONTRACTOR CONTRACTORS David R. Liskowsky Carter Blakey Arlington, VA Editor Bethesda, MD Theodore J. Cicero Washington University School of Medicine Stephen Dinwiddie Washington University School of Medicine William J. McBride IndianaUniversity School of Medicine Theodore Reich Washington University School of Medicine c ontents

1 Executive Summary 1 Drug Action 2 Genetic Factors 6 Role of Learining 7

2 Basic Concepts 9 The Brain Reward System 10 Neuroadaptive Responses 11 Abuse Liability 13 Role of Learning 15 Chapter 2 References 16

3 The Neuropharmacology of Drugs of Abuse 19 Neurophannacology 20 Drugs of Abuse 21 summary 35 Chapter 3 References 36

4 Genetics 39 Do Inherited Factors Exist? 40 What Is Inherited? 43 Summary 50 Chapter 4 References 51

APPENDIXES

A The Drug Evacuation Committee of the College on Problems of Drug Dependence 59 B Acknowledgments 61

VI Executive Summary 1

ubstance abuse and addiction are complex phenomena that defy simple explanation or description. A tangled interaction of factors contributes to an individual’s seeking out, using, and perhaps subsequently abusing drugs.s Since more individuals experiment with drugs than eventually develop substance abuse problems, great interest persists in understanding what differentiates these groups. Factors that can play a role in drug abuse susceptibility include a person psychological makeup (e.g., self-esteem, propensity to take risks, irnpulsivity, depression), biological response to drugs and environmental situation (e.g., peer groups, family organization, socioeconomic status), and the availability of drugs. The exact combination of elements that leads to substance abuse and addiction varies among individuals. Regardless of the mix of contributing factors, the actions and effects that drugs of abuse exert underlie all substance abuse and addiction. In order to understand substance abuse and addiction one must first understand how drugs work in the brain, why certain drugs have the potential for abuse, and what, if any, biological differences exist among individuals in their susceptibility to abuse drugs. While numerous factors ultimately contribute to an individual’s drug-taking behavior, understanding the biological components is crucial to a better comprehen- sion of substance abuse and addiction. In this background paper, the Office of Technology Assessment (OTA) describes the biological components of substance abuse and addiction. Two biological factors contribute to substance abuse and w addiction: the effects drugs of abuse exert on the individual, and the biological status of the individual taking drugs. The former

1 2 I Biological Components of Substance Abuse and Addiction

Box l-A–Neuropharmacology Neurons are the cells that process information in the brain. Neurotransmitters are chemicals released by neurons to communicate with other neurons. When a neuron is activated it releases a neurotransmitter into the synapse, the gap between two neurons (figure l-l). The molecules of the neurotransmitter move across the synapse and attach, or bind, to proteins called receptors in the outer membrane of an adjacent ceil. Once a neurotransmitter activates a receptor, it unbinds from the receptor and is removed from the synapse. This is done either by the neurotransmitter being taken backup into the neuron that released it or by its being chemically broken down. For each neurotransmitter in the brain, there are several specific receptors to which it can attach. Binding by the neurotransmitter activates the receptor. Receptors can be linked to a variety of membrane and cellular mechanisms that are turned on or off by the activation of the receptor. while receptors are specific fora neurotransmitter, there maybe a variety of receptor subtypes, linked to different cellular mechanisms and to different neuronal circuits, that all respond to the same neurotransmitter. In this way one neurotransmitter can have diverse effects indifferent areas of the brain. Many chemicals have been identified as neurotransmitters. Sores are of particular relevance to the rewarding properties of drugs of abuse. These include dopamine, norepinephrine, serotonin, opioids and other neuropeptides, gamma amino butyric add (GABA), and glutamate. A neuron can have thousands of receptors for many different neurotransmitters. Some neurotransmitters activate neurons (excitatory neurotransmitters), while others decrease neuron activity (inhibitory neurotransmitters). Sometimes a receptor for one neurotransmitter can affect a receptor for another neurotransmitter. In such cases, the receptors are biochemically coupled: the activation of one modulates the function of the other, either increasing or decreasing its activity. A neuron can also have receptors for the neurotransmitter it releases. Such receptors are acted on by the neuron’s own neurotransmitter to regulate the release of the neurotransmitter. Thus, these so-called autoreceptors act as a feedback mechanism to regulate a neuron’s activity. The activity ofa neuron will be determined by the cumulative activity of all of its various receptors. Drugs that work in the brain, including drugs of abuse, alter normal neuropharmacological activity through a varietyofdifferent mechanisms. They can affect the production, release, or reuptake of a neurotransmitter, they can mimic or block the action of a neurotransmitter at a receptor, or they can interfere with or enhance the activity of a membrane or cellular mechanism associated with a receptor. Prolonged drug use has the potential to alter each of these processes. SOURCE: office of Technology Assessment, 1993. relates to the acute mechanisms of action of drugs drugs is that most of these drugs act, at least in of abuse in the brain and the long-term effects that part, on those areas of the brain that mediate occur after chronic exposure. The latter pertains feelings of pleasure and reward (box l-B). to an individual’s biological constitution, most The ability to induce activity in the so-called importantly the presence of inherited characteris- brain reward systems gives drugs of abuse posi- tics, which affects that person’s response to a tive reinforcing actions that provoke and support drug. their continued use and abuse. Reinforcement is defined as the likelihood that the consequences of DRUG ACTION taking the drug will increase the behavior directed toward seeking that drug. Put more simply, I Acute Actions individuals who use drugs experience some Drugs of abuse alter the brain’s normal balance effect, such as pleasure, detachment, or relief and level of biochemical activity (box l-A). What from distress, that initially establishes and then separates drugs of abuse from other psychoactive maintains drug self-administration. The con- Chapter l—Executive Summary | 3

Figure l-l—The Synapse and All of these drugs have strong reinforcing proper- Associated Structures ties. Phencyclidine (PCP) is also a strong reinforcer but its relationship, if any, to activity in TT MCLP has not been established. Other drugs are either weak reinforcers or have not been shown to support self-administration in animal experiments. Nicotine activates dopamine neurons in the mesocorticolimbic system. However, when compared with cocaine or amphetamine, this effect is modest. Likewise, caffeine is a weak reinforcer, but the precise mechanisms of its reinforcement are unclear. Finally, while cannabis and lysergic acid diethylamide (LSD) produce positive effects that clearly support their use, there is currently little empirical evidence that they act as reinforcers in controlled experiments.

# Chronic Actions Neurotransmitters Receptors Changes occur in the brain when it is exposed Receiving cell to drugs. Beyond their immediate, rewarding SOURCE: Office of Technology Assessment, 1993. properties, drugs of abuse, when used on a chronic, long-term basis, can cause either perma- sequence of taking the drug enhances the prospect nent changes in the brain or alterations that may that it will continue to be used for some real or take hours, days, months, even years to reverse on perceived effect and eventually compulsive self- drug cessation. These changes are adaptive re- administration. In fact, the capacity of a drug to sponses related to the pharmacological action of support self-administration in experimental ani- a given drug that occur in the brain to counter the mals is a measure of the drug’s strength as a immediate effects of a drug. reinforcer. Tolerance develops to a drug when, following While growing evidence indicates that the a prolonged period of use, more of the drug is brain reward system likely plays a role in the required to produce a given effect. Tolerance reinforcing properties of most drugs of abuse, the occurs with many types of drugs and is a common, precise mechanisms involved in all drugs of abuse but not necessary, characteristic of drugs of have yet to be completely described. The reward- abuse. Tolerance can contribute to drug-taking ing properties of stimulant drugs such as cocaine behavior by requiring that an individual take and amphetamines are due to a direct increase in progressively larger doses of a drug to achieve a the activity of the neurotransmitter dopamine in desired effect. the mesocorticolimbic dopamine pathway (see Dependence occurs when, with prolonged use box l-B). Opiates, on the other hand, indirectly of a drug, neurons in the brain adapt to the drug’s stimulate dopamine activity by activating other presence such that the use of the drug is now neurotransmitter pathways, which in turn increase required to maintain normal function in the cells. dopamine activity in the mesocorticolimbic path- On abrupt withdrawal of the drug, the neuron way (MCLP). Similarly, alcohol, barbiturates, behaves abnormally and a “withdrawal syn- and benzodiazepines also indirectly activate MCLP. drome” ensues, Generally, the withdrawal syn- 4 I Biological Components of Substance Abuse and Addiction

1 An~~a@~i~ ofoelislnthe brafnthat share thesarneanatomlcal ~a~ ~~~-; * Sarrm funotlon. SOURC~Q.F. Korb, ‘DrugaofAbuoa:Anabmy, Phannaodogy, and FunotbnofRcward Pathwayq” ~bh~~ l&177-lS4, 19DZ G.F. Koob, “thud Mdanlam d Drug Rdnfo romtnt” P.W. Kal!w, ad H.H. Satwun (ocIB.), 7kikudddw d LMl#afldAkohol Adotfm AnmhofthoAm?ican Aca&ny of Sdanoss S54:171-191, 1992.

drome is characterized by a series of signs and born cocaine users that the drug’s euphoric symptoms that are opposite to those of the acute actions diminish with repeated use. Tolerance effects of the drug. Withdrawal creates a craving also develops to the effects, including the rein- or desire for the drug and plays a very strong role forcing properties, of opiates and alcohol. in recurrent patterns of relapse, in maintaining A withdrawal syndrome of varying severity is drug-seeking behavior to forestall the withdrawal associated with most drugs of abuse. Barbiturates, syndrome, and in the need to reestablish some alcohol, stimulants, opiates, and benzodiazepines sense of normalcy. produce pronounced and sometimes severe with- Sensitization occurs when the effects of a given drawal symptoms, while those for nicotine and dose of a drug increase after repeated administra- caffeine are less intense. A mild withdrawal is tion. Thus, sensitization is the opposite of toler- associated with cannabis use, while there is no ance. Sensitization to a drug’s behavioral effects evidence of a withdrawal syndrome related to could play a significant role in supporting drug- LSD. taking behavior. For example, while tolerance to some of the I Abuse Liability effects of cocaine and amphetamines develops, The abuse liability of a drug is a measure of the sensitization to other of their effects can also likelihood that its use will result in drug addic- occur. Also, while it is unclear horn available data tion. Many factors ultimately play a role in an whether tolerance develops to cocaine’s reinforc- individual’s drug-taking behavior; nevertheless, ing effects, the notion is supported by some the abuse potential of a drug is related to its experimental evidence and anecdotal reports intrinsic rewarding properties and/or the neu- Chapter l–Executive Summary | 5

roadaptive responses that result from its pro- Figure 1-2—The Mesocortlcolimbic Pathway longed use. Drugs can be tested and screened for their abuse liability using animals as models. The criteria that can be evaluated to classify a drug as having significant abuse potential are pharmacological equivalence to known drugs of abuse, demonstration of reinforcing effects, tolerance, and physical dependence. The capacity to produce reinforcing effects is essential to any drug with significant abuse potential, whereas toler- Ventral\ ance and physical dependence most commonly tegmental v occur but are not absolutely required to make such area a determination. The mesocorticolimbic pathway from the ventral tegmental area to the nucleus accumbens and the frontal cortex is a key component of the brain reward system for drug reinforcement. SELF-ADMINISTRATION SOURCE: Office of Technology Assessment, 1993. The predominant feature of all drugs with significant abuse potential properties is that they are self-administered. In fact, self-administration a drug from a placebo show a remarkable ability of a drug to the point when the behavior becomes to distinguish that drug from other drugs with obsessive and detrimental to the individual is the different properties. These procedures also permit primary criterion that must be met to classify a a determination of whether the subject considers drug as having significant potential for addiction. the drug to be the pharmacological equivalent of In addition to self-administration, another con- another drug. Pharmacological equivalence refers tributing factor to abuse liability is the notion of to the fact that drugs of a particular class, such as craving and the tendency of individuals to relapse opiates, stimulants, and depressants, cause a to drug use during withdrawal. Although craving series of effects on the brain and other organs that is a difficult term to quantify, once a drug is collectively constitute their pharmacological pro- voluntarily or involuntarily withdrawn, the desire file. to take the drug can play a role in the relapse to substance abuse. Animals can be readily trained to self- DEPENDENCE AND TOLERANCE administer drugs. Animal models of self- Dependence and tolerance can readily be administration provide a powerful tool that can induced in animals by chronic administration of give a good indication of the abuse liability of drugs. Following abrupt withholding of a drug, a new or unknown drugs. These models also permit withdrawal syndrome will often develop and the an examination of the behavioral, physiological, motivation for self-administration of the drug and biological factors that lead to sustained may be increased. Thus, the capacity of a drug to self-administration. induce neuroadaptive motivational changes can be assessed. Furthermore, since the understand- DRUG DISCRIMINATION ing of the neuroadaptive changes that take place Another tool in the assessment of abuse liabil- during the development of physical dependence ity of drugs is drug discrimination, which refers to and tolerance are poorly understood in humans, the perception of the effects of drugs. Specifi- animal models offer a unique opportunity to carry cally, animals or humans trained to discriminate out experiments designed to address these issues. 6 | Biological Components of Substance Abuse and Addiction

GENETIC FACTORS vulnerability to the addictive properties of other Progress in understanding the genetics of drugs of abuse, evidence from animal studies various conditions and diseases has brought with confirms the role of a genetic influence on the use it a realization that substance abuse and addiction and abuse of drugs other than alcohol. The study probably involve a genetic component. That is, of nonalcoholic drug abuse in humans has been hereditary biological differences make some indi- difficult due to substantially lower population viduals either more or less susceptible to drug prevalence and differences in availability and, dependency than others. While it seems likely hence, exposure to these agents. Investigation in that inherited differences exist, a genetic compo- this area is further hampered by the complexity of nent alone is insufficient to produce substance subjects’ drug use: most drug abusers have used abuse and addiction. multiple agents. This has led researchers either to Unlike disorders, such as Huntington’s disease concentrate on one class of drug or to treat all and cystic fibrosis, that result from the presence illicit drug use as equivalent. The tendency to of alternations in a single gene, a genetic compo- lump all illicit drugs into one category makes nent of substance abuse is likely to involve results difficult to interpret or compare. multiple genes that control various aspects of the biological response to drugs or physiological I What Is Inherited? predisposition to become an abuser. In addition, While study results support the role of a genetic the complex nature of drug dependency, involv- component in alcoholism and probably other drug ing many behavioral and environmental factors, abuse, they provide no information about what indicates that any genetic component acts in exactly is inherited. For example, do individuals consort with other nongenetic risk factors to with a family history of drug abuse have an contribute to the development of substance abuse increased susceptibility or sensitivity to the ef- and addiction. Thus, the presence of a genetic fects of drugs with reinforcing properties? If a factor does not ensure drug addiction nor does its susceptibility exists, what are its underlying absence guarantee protection from drug addic- biological mechanisms? Information about inher- tion. ited biological mechanisms is most easily derived Two questions arise when considering a ge- from studies of animals bred to have differing netic component to substance abuse and addic- responses to various drugs. However, in humans, tion: Do inherited factors exist? And, if so, what few studies have examined the relationship be- are they? To date, much of the work done in this tween inherited behavioral traits and the inherited field relates to alcoholism. Less is known about biological mechanisms that might underlie them. the genetic aspects of the abuse of other drugs. In the case of alcohol, studies suggest that low doses of alcohol are more stimulating and pro- I Do Inherited Factors Exist? duce a stronger positive reward in rats bred to Results from family studies, twin studies, and have a high preference for alcohol as compared adoption studies as well as extensive research on with normal rats. Experimental data indicate that animal models indicate that heredity influences this may be due to inherited differences in the normal as well as pathological use of alcohol. mesocorticolimbic dopamine system (see box Animal studies have established that genetic l-B) and an inherited increased response of this factors contribute to alcohol preference, the system when exposed to alcohol. Also, alcohol- reinforcing actions of alcohol, alcohol tolerance, preferring rats have been found to have different and alcohol physical dependence. While few levels of activity in other neurotransmitter sys- studies have examined the genetic component of tems that modulate activity in the mesocorti- Chapter l–Executive Summary | 7

colimbic system. In humans, studies of college- brain activity and processes will facilitate these aged individuals indicate that low initial sensitiv- studies. ity to alcohol may be a predictor for alcoholism later in life. Studies using the technique of genetic linkage ROLE OF LEARNING analysis 1 have attempted to identify genes that The learning that occurs when an individual might be associated with alcoholism in humans. takes drugs is an important contributing force in However, the findings of these studies are incon- the continued use and craving of drugs. Drugs of clusive. While some studies have reported a link abuse produce positive or pleasurable feelings in between alcoholism and a gene that regulates the the user and have reinforcing properties. In number of a type of dopamine receptor in the addition to these effects, drugs of abuse produce brain, others have not. The reason for this changes in numerous organ systems such as the discrepancy is unclear, but one study has found a cardiovascular, digestive, and endocrine systems. relationship between the presence of the gene not Both the behavioral and physiological effects of only in alcoholism, but also in other disorders a drug occur in the context of an individual’s such as autism, attention deficit hyperactivity drug-seeking and drug-using environment. As a disorder, and Tourette’s syndrome. Thus, the result, environmental cues are present before and presence of the gene may cause an alteration in during an individual’s drug use that are consist- the brain dopamine system that somehow exacer- ently associated with a drug’s behavioral and bates or contributes to alcohol abuse, but is not physiological effects. With repetition the cues uniquely specific for alcoholism. become conditioned stimuli, that on presentation, Fewer studies have focused on possible inher- even in the absence of the drug, evoke automatic ited biological mechanisms associated with the changes in organ systems and behavioral sensa- abuse of other drugs. For example, strains of rats tions that the individual experiences as drug and mice that differ in their sensitivity to the craving. These associations are difficult to re- reinforcing effects of cocaine and in their cocaine- verse. In theory, repeated presentation of the seeking behavior have also been observed to have environmental cues, absent the drug, should differences in the number of dopamine-contain- extinguish the conditioned association. Animal ing neurons and receptors in certain brain areas. studies indicate that extinction is difficult to Also, a comparison of one strain of rat that achieve and does not erase the original learning, self-administers drugs of abuse at higher rates As a result, even once established, the extinction than another strain found that the higher self- is readily reversed. administering strain exhibited differences in the Also, it has long been known that conditioning intracellular mechanisms that control activity in occurs in relation to the withdrawal effects of some of the neurons in the brain reward system as drugs. This phenomenon, termed conditioned compared with the low self-administering strain. withdrawal, results from environmental stimuli Additional studies exploring the role of genes in acquiring the ability, through classical condition- drug response are needed to more fully under- ing, to elicit signs and symptoms of pharmacolog- stand the full range of biological factors associ- ical withdrawal. The emergence of withdrawal ated with drug abuse. The recent development of symptoms as a result of exposure to conditioned new and more sensitive techniques to analyze cues can contribute to drug use relapse by

1 Genetic linkage studies establish an association between an area of a specific chromosome and the expression of a trait. Linkage analysis uses spec~Ic markers that identify the area on a chromosome that might contain the gene of interest. If the marker consistently occurs in association with the expressed trai~ then it is likely that the gene of interest is in that chromosomal region. 8 I Biological Components of Substance Abuse and Addiction

motivating an individual to seek out and use sion further drug use even after successful detoxi- drugs. fication. Thus, exposure to environmental cues associ- The complexity of human responses to drugs of ated with drug use in the past can act as a priming abuse, coupled with the number of drugs that are force to motivate voluntary drug-seeking behav- abused, complicates understanding of the role of ior. Drug conditioning can help explain the fact biology in drug use and abuse. Nevertheless, that many drug abusers often return to environ- scientists know the site of action of many drugs in ments associated with drug use, even after being the brain, and sophisticated new devices are counseled not to. The effects of the environmental expected to improve that understanding. A ge- stimuli can be similar to the priming effects of a netic component to drug use and abuse is likely, low dose of the drug or result in withdrawal but it has not been fully characterized. symptoms. In either case these stimuli can occa- Basic Concepts 2

imilar to other psychoactive drugs, drugs of abuse alter the brain’s normal balance and level of biochemical activity. This can include mimicking the action of naturally occurring neurotransmitters (chemicals in the brain that sends messages from one nerve cell to another), blocking neurotransmitter action, or in other ways altering the normal chemical actions that mediate the transmission of information within the brain. The ultimate effect is to either elevate or depress activity in different brain regions (see ch. 3). What separates drugs of abuse from other psychoactive drugs is that these drugs act, at least in part, on those areas of the brain that mediate feelings of pleasure and reward. Inducing activity in the so-called brain reward system gives drugs of abuse positive reinforcing actions that provoke and support their continued use and abuse. Beyond their immediate, rewarding properties, drugs used on a chronic, long-term basis can cause either permanent changes in the brain or alterations that may take hours, days, months, even years, to reverse on drug cessation. These changes are adaptive responses that occur in the brain to counter the immediate effects of a drug. When drug taking is stopped, these changes are often manifested as effects that are opposite to the initial pleasurable drug response. The continued administration of drugs to avoid the aversive effects of drug cessation also contributes to an individual’s addiction to a drug. Their immediate and long-term effects imbue drugs of abuse with reinforcing properties. Reinforcement is defined as the likelihood that the consequences of taking the drug will increase I the behavior directed toward seeking that drug (6). Put more I 10 I Biological Components of Substance Abuse and Addiction

simply, individuals who use drugs experience Most drugs of abuse, either directly or indi- some effect, such as pleasure, detachment, or rectly, affect the brain reward system. This is relief from distress, that initially establishes and evident by the fact that administration of most then maintains drug use. Thus, the consequence drugs of abuse reduces the amount of electrical of taking the drug enhances the prospect that it stimulation needed to produce self-stimulation will continue to be used for some real or perceived responding (28). effect and also establishes a need state, hence, The reward system is made up of various brain engendering compulsive self-administration. structures. The central component is a neuronal In addition to their reinforcing effects, drugs of pathway that interconnects structures in the mid- abuse can have a variety of pharmacological dle part of the brain (i.e., hypothalamus, ventral actions in other areas of the brain and the body. tegmental area) to structures in the front part of The ultimate effect of a drug will also be shaped the brain (i.e., frontal cortex, limbic system) by other factors including the dose of the drug, the (15,16). A key part of this drug reward pathway route of administration, the physiological status appears to be the mesocorticolimbic pathway of the user, and the environmental context in (MCLP) (figure 2-l). MCLP is made up of the which the drug is taken. The subjective experi- axons of neuronal cell bodies in the ventral ence of the drug user and his or her overt behavior tegmental area projecting to the nucleus accum- is the result of a combination of these factors and bens, a nucleus in the limbic system. The limbic the drug’s pharmacological action. system is a network of brain structures associated with control of emotion and behavior, specifically perception, motivation, gratification, and mem- THE BRAIN REWARD SYSTEM ory. MCLP also connects the ventral tegmental Eating, drinking,g,sexual, and maternal behav- area with parts of the frontal cortex (medial iors are activities essential for the survival of the prefrontal cortex). Ventral tegmental neurons individual and the species. Natural selection, in release the neurotransmitter doparnine to regulate order to ensure that these behaviors occur, has the activity of the cells in the nucleus accumbens imbued them with powerful rewarding properties. and the medial prefrontal cortex. Other parts of The brain reward system evolved to process these the reward system include the nucleus accumbens natural reinforcers. and its connections with other limbic structures Studies have shown that direct stimulation of like the amygdala and hippocampus, as well as to the areas of the brain involved in the reward other regions in the front part of the brain (i.e., system, in the absence of any goal-seeking be- substantial innominata-ventral palladium). There havior, produces extreme pleasure that has strong are also connections from the nucleus accumbens reinforcing properties in its own right (17). Such down to the ventral tegmental area. Finally, other stimulation activates neural pathways that carry neuronal pathways containing different neuro- natural rewarding stimuli. Animals with elec- transmitters (i.e., serotonin, opioids, gamma amino trodes implanted in these areas in such a way that butyric acid (GABA), glutamate, peptides) regu- electrical impulses produce a pleasurable sensa- late the activity of the mesocorticolimbic dopa- tion will repeatedly press a bar, or do any other rnine system and are also involved in mediating required task, to receive electrical stimulation. the rewarding properties of drugs of abuse. The fact that animals will forego food and drink These structures and pathways are thought to to the point of death or will willingly experience play a role in the reinforcing properties of many a painful stimulus to receive electrical stimulation drugs of abuse, although the precise mechanisms of the reward system attests to the powerful involved in all drugs of abuse lack a thorough reinforcing characteristics of the reward system. description. The mesocorticolimbic dopamine Chapter 2—Basic Concepts | 11

Figure 2-l—The Mesocorticolimbic Pathway have motivational consequences that contribute and play a role in an individual’s subsequent drug-taking behavior. The specific details of the biological mechanisms that underlie these phe- Frontal -—--- nomena are not completely understood, but recent cortex advances in neuroscience research have begun to unravel how neuroadaptive responses manifest Nucleus — themselves for various drugs of abuse. As with the accumbens immediate rewarding properties of these drugs, some evidence suggests that there may be common underlying mechanisms to the neuroadaptive tegmental v area responses related to reward mechanisms of various drugs of abuse (2). What follows is a general The mesocorticolimbic pathway from the ventral tegmental area to the nudeus accumbens and the frontat cortex is a key description of neuroadaptive responses. Specific component of the brain reward system for drug reinforcement. details of possible biological mechanisms associ- SOURCE: Off Ice of Tdnobgy Assessment, 1993. ated with the neuroadaptive responses of various drugs are provided in chapter 3. pathway appears to be critical in the rewarding properties of stimulant drugs such as cocaine and | Tolerance amphetamines (15,16,29). Also, both the ventral Tolerance develops to a drug when, following tegmental area and the nucleus accumbens appear a prolonged period of use, more of the drug is to be important for opiate reward (7,15,16), while required to produce the same effect (10,14). these same structures and their connections to Tolerance occurs with many types of drugs. It is other limbic areas, like the amygdala, may play a a common, but unnecessary, characteristic of role in the rewarding properties of barbiturates drugs of abuse. There are two types of tolerance: and alcohol (15,16,20). Further details about the dispositional (pharmacokinetic) and pharmaco- brain areas involved in the rewarding properties dynamic. of various drugs of abuse are provided in chapter 3. DISPOSITIONAL Dispositional tolerance develops when the NEUROADAPTIVE RESPONSES amount of drug reaching active sites in the brain Exposure to drugs causes changes in the brain. is reduced in some way. Generally, this arises These changes are alterations in neurochemical from an increased breakdown of the drug or a mechanisms related to the pharmacological ac- change in its distribution in the rest of the body. tion of a given drug. Often the change represents Thus, more drug must be taken to achieve the a compensatory adjustment in the brain to return same blood levels or concentrations at the active the balance of activity back to normal after initial sites in the brain. exposure to the drug. Most drugs of abuse involve complex actions in the brain resulting in a variety PHARMACODYNAMIC of behavioral effects. Often, the type of neu- This form of tolerance represents a reduced roadaptive response that occurs to a drug is response of the brain to the same level of drug. It opposite to its acute effects. Thus, the positive develops during the continued and sustained reinforcing properties of drugs are replaced by the presence of the drug. It may be that the mecha- negative reinforcing properties of withdrawal. nism of adaptation may differ from drug to drug This indicates that neuroadaptive responses can and depend on the original mechanism of action 12 I Biological Components of Substance Abuse and Addiction

of a given drug. The net effect is that more drug | Residual Tolerance and Dependence is required to overcome this new neuronal adapta- In general, expression of tolerance and depend- tion to produce an equivalent pharmacologic ence has been considered to be rate-limited in that effect. tolerance to most drugs gradually dissipates with Although dispositional tolerance represents a time as the brain readapts to the disappearance of component of tolerance to some drugs (e.g., the drug and withdrawal peaks within hours or alcohol, barbiturates), in most cases much or all days after discontinued use and then dissipates. of the tolerance that develops to drugs with However, substantial evidence indicates that significant abuse potential can be attributed to there may be persistent or residual neuroadapta- pharmacodynamic tolerance (10,14). Tolerance tion that lasts for months or years (10,27). For can contribute to drug-taking behavior by requir- example, craving and drug-seeking behavior have ing that an individual take larger and larger doses been reported to last for years with nicotine, of a drug to achieve a desired effect. alcohol, and cocaine suggesting some residual effect of drug use that may or may not dissipate I Dependence with time. Moreover, there is a phenomenon that characterizes drug-dependent individuals. Specif- armacodynamic tolerance, dependence Like ph ically, with repeated cycles of abstinence and also refers to a type of neuroadaptation to drug reinitiation of drug use, the time required to elicit exposure. Dependence differs in that, with pro- drug dependence grows shorter and shorter. longed use of a drug, cells in the brain adapt to its Furthermore, there is evidence that the adminis- presence such that the drug is required to maintain tration of naloxone, a drug that blocks the actions normal cell function. On abrupt withdrawal of the of opiates, may elicit a withdrawal syndrome in drug, the neuron behaves abnormally and a individuals who have abstained from use for withdrawal syndrome ensues. Generally, the with- extensive periods of time. These data indicate that drawal syndrome is characterized by a series of some residual neuroadaptive changes induced by signs and symptoms that are opposite to those of drugs persist for as yet undefined periods of time. the acute effects of the drug. For example, on Little information is available about the mecha- withdrawal, sedative drugs produce excitation nisms involved in this effect, but it is clear that and irritability. Conversely, stimulants produce residual neuroadaptive changes may persist for profound depression on withdrawal. extended periods of time in former drug users and The magnitude of the withdrawal syndrome that they may account for the striking relapses that varies from drug to drug. With some drugs very occur in long-term abstinent drug-dependent mild withdrawal occurs, whereas with others individuals. (e.g., alcohol, barbiturates) the withdrawal syndrome can be so severe that it is life-threatening. No matter the severity of the withdrawal syn- I Sensitization drome, its existence can create a craving or desire Sensitization occurs when the effects of a given for the drug and dependence can play a very dose of a drug increase after repeated administra- strong role in recurrent patterns of relapse, in tion. Thus, sensitization is the opposite of toler- maintaining drug-seeking behavior to forestall ance. Sensitization to a drug’s behavioral effects the withdrawal syndrome, and in the need to can play a significant role in supporting drug- reestablish some sense of normalcy. taking behavior. Chapter 2–Basic Concepts | 13

ABUSE LIABILITY humans (l). Laboratory methods for abuse poten- The abuse liability of a drug is a measure of the tial evaluation in humans are also well developed, likelihood that its use will result in drug addic- and this is an area of active research(8). However, tion. While many factors ultimately play a role in factors such as the heterogeneity of drug using an individual’s drug-taking behavior, the abuse populations, the use of multiple drugs, and the potential of a drug is related to its intrinsic other biological, social, and environmental fac- rewarding properties and the neuroadaptive re- tors involved in human drug use make human sponses that result from prolonged use. Drugs can studies complex. be tested and screened for their abuse liability. At first glance, it would seem impossible to The conceptual framework to screen drugs for mimic in an animal the highly complex syndrome their abuse potential is virtually the same for all of drug abuse in humans. However, paradoxi- drugs: opiates, stimulants, depressants, hallucino- cally, the apparent limitations of animal models gens, and inhalants (l). The criteria that can be are actually their strengths. Specifically, the evaluated to classify a drug as having significant simplicity of an animal model obviates the abuse potential are: pharmacological equivalence problems inherent in the complexity of humans: to known drugs of abuse, demonstration of the experimenter has strict control of environ- reinforcing effects, tolerance, and physical de- mental factors, drug use experience and patterns, pendence. The capacity to produce reinforcing and individual differences that permit study of the effects is essential to any drug with significant pharmacological and biological mechanisms as- abuse potential, whereas tolerance and physical sociated with the development of addiction po- dependence most commonly occur but are not tential. Thus, the use of animal models permits absolutely required to make such a determination. the highly complex syndrome of human drug Testing new pharmaceuticals for their abuse addiction to be dissected into separate compo- potential is an important step in new drug nents without the intrusion of a series of con- development. The emphasis of many major phar- founding variables found in humans. maceutical firms today is on the development of In terms of the validity of animal models as a new and safer drugs for pain reduction and in the means of studying human drug addiction, an development of psychoactive compounds to treat excellent correlation exists between predicting brain disorders. In particular, scientific strides in the abuse liability of specific classes of drugs in understanding the brain, neurological disease, animals and humans (12). However, it must be psychiatric disturbances, and aging are fueling recognized that animal models are not perfect research into treatment of brain disorders. As such and, in fact, there are examples of drugs that psychoactive compounds become available, they proved to have significant abuse potential in must be screened for abuse potential. The abuse humans, whereas the preclinical testing in ani- liability assessment of new products is not simply mals revealed relatively minimal abuse potential at the discretion of the manufacturer. As dis- (6,10,14). Thus, the ultimate answer to the issue cussed in appendix A, various Federal regulatory of whether a drug has significant abuse potential laws mandate such testing and Federal regulatory is long-term experience with the drug once it has agencies are charged with seeing that testing is become available, either legally or illegally. carried out. Nevertheless, animal models serve as the only Animal models are generally used to screen for practical means of initially screening drugs for the abuse potential of new drugs in earlier stages abuse liability and have proven to be the most of drug development or to evaluate abuse poten- effective means of detecting whether there is tial in drugs that cannot be readily studied in likely to be a problem in humans. 14 I Biological Components of Substance Abuse and Addiction

Self=Administration drugs have reinforcing effects. In addition, the The predominant feature of all drugs with efficacy of drugs as reinforcers can be evaluated significant addiction-producing properties is that using the amount of work animals will perform to they are self-administered (3,5,9,11). In fact, obtain drug injections or how they make selec- self-administration of a drug to the point when the tions between drug reinforcers. By making com- behavior becomes obsessive and detrimental to parisons of the self-administration rates of un- the individual is the primary criterion for classify- known compounds with known standard refer- ing a drug as having significant potential for ence drugs, it is often possible to estimate the addiction. In addition to self-administration, an- reinforcing property of the drug relative to the other predictor of drug addiction is the notion of standard. Thus, by using self-administration tech- craving and the tendency to relapse or increase niques, one can assess the relative reinforcing use during withdrawal (6, 10,14). Although crav- strengths of a drug and also examine the behav- ing is a difficult term to quantify, once a drug is ioral, physiological, and biological factors that voluntarily or involuntarily withdrawn, the desire lead to sustained self-administration. to take it can play a role in the relapse to substance abuse. As previously mentioned, the reinforcing properties of the drug underlying craving maybe I Drug Discrimination shifted from the pattern established during the Drug discrimination is another tool used in the initial, early phase of drug addiction. Specifically, assessment of abuse liability of drugs in animals the drug may have initially been self-adminis- (3,6). Drug discrimination refers to the perception tered for its pleasurable effects but may eventu- of the effects of drugs. Specifically, animals or ally be self-administered to relieve the discomfort humans trained to discrimin ate a drug from associated with withdrawal. Thus, the primary placebo show a remarkable ability to distinguish motivation for using the drug can be that the between the effects of the drug from other drugs individual needs the drug to function normally. possessing different properties. The procedures Animals can be readily trained to self- also permit a determination of whether the animal administer drugs (6). Which experimental tech- considers the drug to be the pharmacological nique is used depends on the class of compounds, equivalent of another drug. Pharrnacologicalequiv- a drug’s normal route of administration in hu- alence refers to the fact that drugs of a particular mans, and methodological concerns (e.g., solubil- class, such as opiates, stimulants, and depres- ity of the drug). While the reasons animals initiate sants, produce a unique series of effects on the drug-seeking behavior are dictated by the experi- brain and other organs that collectively constitute mental situation, rather than intrinsic disposi- their pharmacological profile. Thus, although tional factors as in humans, the pattern of use once drugs may vary considerably in their chemical established fulfills all of the criteria of drug structure, similar pharmacological effects indi- addiction: compulsive drug-seeking behavior to cate specifically how they actually interact with the point of detrimental effects on the animal and and influence the behavior of the intact organism. enhanced attempts of self-administration during While animals cannot express whether a drug’s withdrawal. subjective effects are similar or dissimilar to The technique of self-administration is a pow- another, various behavioral experiments can be erful tool and provides a good indication of the used to determine whether an animal perceives abuse liability of new or unknown drugs (l). For drugs to be pharmacologically dissimilar or example, substitution studies can be used to equivalent. For example, animals can clearly determine whether, and over what dosage ranges, distinguish opiates from stimulants or other Chapter 2–Basic Concepts I 15

depressants, but may be unable to distinguish one final drug testing be carried out in humans. opiate of the same type from another. Nevertheless, animal testing is an accepted predictor of abuse potential in humans and must be | Dependence and Tolerance carried out to provide the basis for additional screening in humans. Dependence and tolerance can readily be induced in animals by either volitional or passive In terms of rating the abuse liability of drugs in means (13,14). Specifically, using a self- animals, the degree of abuse liability that can be administration model, animals often will develop expected from a drug of abuse can be determined tolerance and dependence characterized by in- using the animal testing procedures outlined creased amounts of drug self-administration and/ above. For example, by comparing the degree to or enhanced rates of self-administration. Follow- which a drug satisfies the criteria outlined above, ing abrupt withdrawal of the drug, a withdrawal such as the amount of work that will be performed syndrome will often develop and, if given the to self-administer the drug and the strength of the opportunity, self-administration rates will be physical dependence, general conclusions about increased. Alternatively, it is often easier to the abuse potential of an unknown drug by either induce tolerance and physical dependence pas- comparison to drugs of a similar class or different sively by injecting large amounts of drug into classes of drugs can be made. animals for prolonged periods of time. In this while tests show that a drug has abuse poten- case, neuroadaptation occurs quickly and predict- tial, the problem it poses in humans ultimately ably. This technique has the advantage that the depends on the overall effects of the drug and the experimenter can exercise complete control of extent to which self-administration of the drug doses and times required to produce tolerance and represents a problem to the individual or society. dependence. In either case, it is possible to induce Relative abuse potential and its severity must be neuroadaptation in animals that can then be considered in terms of the consequences not only experimentally manipulated. Furthermore, since to the person, but also in the societal and the understanding of the neuroadaptive changes environmental context in which it occurs. that take place during the development of tolerance and physical dependence are poorly under- ROLE OF LEARNING stood in humans, animal models offer a unique Another significant contributing force in drug opportunity to carry out experiments designed to abuse is the learning that can occur during an address these issues. individual’s drug-taking activity (18,23). In addition to producing pleasant feelings in I Interpretation of Results in Animals and the user and having rewarding properties, drugs of the Concept of Thresholds abuse produce changes in numerous organ sys- Once a drug has been classified as having tems such as the cardiovascular, digestive, and significant abuse potential, two central questions endocrine systems. Both the behavioral and remain: first, does this information pertain to physiological effects of a drug occur in the humans; and, second, can one rate the relative context of an individual’s drug-seeking and abuse potential of drugs in animals (e.g., Does drug-using environment. As a result, there are drug A have five times the abuse liability of drug environmental cues present before and during an B?). with regard to the frost point, results from individual’s drug use that are consistently associ- animal testing generally have been excellent ated with a drug’s behavioral and physiological predictors of abuse liability of drugs in humans, effects. With repetition the cues become condi- but a small number of exceptions mandate that tioned stimuli, that on presentation, even in the 16 I Biological Components of Substance Abuse and Addiction

absence of the drug, evoke automatic changes in extinguish the conditioned association. Animal organ systems and behavioral sensations that the studies indicate that extinction is difficult to individual may experience as drug craving. This achieve and does not erase the original learning. is analogous to Pavlov’s classical conditioning As a result, once established, the extinction is experiments in which dogs salivate on the cue of easily reversed. Animal studies examining drug a bell, following repeated pairing of food presen- conditioning have found that various aspects of tation with a ringing bell. Evidence for this effect extinguished responses can either be reinstated is seen in numerous studies showing that animals with a single pairing of the drug and environ- seek out places associated with reinforcing drugs mental cue, can be reinstated with a single dose of and that the physiological effects of drugs can be drug in the absence of the environmental cue, or classically conditioned in both animals and hu- can spontaneously recover (23). mans (12). Thus, exposure to environmental cues The biological mechanisms underlying condi- associated with drug use in the past can act as a tioned drug effects are just beginning to be stimulus for voluntary drug-seeking behavior. If described. Recent evidence links the mesocorti- the individual succeeds in finding and taking the colimbic system to these effects. Studies have drug, the chain of behaviors is further reinforced found increased release of dopamine in the by the drug-induced rewarding feelings and the nucleus accumbens associated with anticipated effects of the drug on other organ systems (18). voluntary alcohol consumption (18,19,24,25). Drug conditioning can help explain the fact that Other studies have presented evidence that de- many drug abusers often return to environments struction of MCLP blocks the conditioned rein- associated with drug use, even after being coun- forcing effects of opiates (4,21,22). The excita- seled not to. The effects of the environmental tory amino acid neurotransmitters may also play stimuli can be similar to the priming effects of a a role in drug conditioning effects. As the name dose of the drug. implies, excitatory amino acids are a class of Also, it has long been known that conditioning neurotransmitter that act to stimulate neuronal occurs in relation to the withdrawal effects of activity in the brain. These amino acids have been drugs (26). It was observed that opiate addicts implicated in learning and memory. Injection of who were drug free for months and thus should a drug that blocks the activity of the excitatory not have had any signs of opiate withdrawal, amino acids has been shown to block the develop developed withdrawal symptoms (e.g., yawning, ment of conditioned amphetamine effects (23). sniffling, tearing of the eyes) when talking about Finally, there is evidence that genetic factors may drugs in group therapy sessions. This phenome- play a role in the conditioning phenomena associ- non, termed conditioned withdrawal, results from ated with drug use (see ch. 4). environmental stimuli acquiring the ability, through classical conditioning, to elicit signs and symptoms of pharmacological withdrawal. Con- CHAPTER 2 REFERENCES ditioned withdrawal can also play a role in relapse 1. Balster, R.L., “Drug Abuse Potential Evaluation in Amin”Anunak,’ British Journal of addiction 86: 1549- to drug use in abstinent individuals. The emer- 1558, 1991. gence of withdrawal symptoms as a result of 2. Beitner-Johnson, D., Guitart, X., and Nestler, E.J., exposure to conditioned cues can motivate an “Common Intracellular Actions of Chronic Mor- individual to seek out and use drugs. phine and Cocaine in Dopaminergic Brain Re- Studies have also demonstrated that, once ward Regions, ” P.W. Kalivas, and H.H. Samson established, conditioned associations are difllcult (eds.), The Neurobiology of Drug and Alcohol to reverse (23). In theory, repeated presentation of Addiction, Annals of the American Academy of the environmental cues, without the drug, should Sciences 654:70-87, 1992. Chapter 2–Basic Concepts | 17

3. Bigelow, G.E., andPreston, K. L., “DrugDiscrim- Liability of Drugs in Humans, U.S. Department of ination: Methods for Drug Characterization and Health and Human Services Pub. No (ADM) Classification,’ NIDA Research Monograph #92: 89-1613, M.W. Fishman, and M.K. Mello (eds.) Testing for Abuse Liability of Drugs in Humans, (Washington, DC: U.S. Government Printing U.S. Department of Health and Human Services Office, 1989). Pub. No (ADM) 89-1613, M.W. Fishman, and 12. Johanson, C., Woolverton, W. L., and Schuster, M.K. Mello (eds.) (Washington, DC: U.S. Gov- C.R., “Evaluating Laboratory Models of Drug ernment Printing Office, 1989). Dependence,” Psychopharmacology: The Third 4. Bozarth, M.A., and Wise, R. A., “Intracranial Generation of Progress, H. Meltzer (cd.) (New Self-Administration of Morphine Into the Ventral York, NY: Raven Press, 1987). Tegmental Area of Rats,” Life Sciences 28:551- 13. Kalant, H., “Behavioral Criteria forTolerance and 555, 1981. Dependence,’ The Bases of Addiction, J. Fishman 5. Brady, J. V., “Issues in Human Drug Abuse (cd.) (Berlin: Dahlem Konferenzen, 1988). Liability Testing: Overview and Prospects for the 14. Kalant, H., ‘‘The Nature of Addiction: An Analy- Future,” NIDA Research Monograph #92: Test- sis of the Problem,” Molecular and Cellular ing for Abuse Liability of Drugs in Humans, U.S. Aspects of the Drug Addictions, A. Goldstein (cd.) Department of Health and Human Services Pub. (New York, NY: Springer Verlag, 1989). No (ADM) 89-1613, M.W. Fishman, and M,K. 15. Koob, G. F, “Drugs of Abuse: Anatomy, Pharma- Mello (eds.) (Washington, DC: U.S. Government cology and Function of Reward Pathway s,’ Printing Office, 1989). Trends in Pharmacological Science 13:177-183, 6. Brady, J.V., and Lucas, S.E. (eds.), NIDA Re- 1992. search Monograph #52: Testing Drugs for Physi- 16. Koob, G. F., and Bloom, F. E., “Cellular and cal Dependence Potential and Abuse Liability, U.S. Department of Health and Human Services Molecular Mechanisms of Drug Dependence,” Publication No. (ADM) 84-1332 (Washington, Science 242:715-723, 1988. DC: U.S. Government Printing Office, 1984). 17. Liebman, J.M., and Cooper, S.J. (eds.), The 7. Di Chiara, G., and North, R. A., “Neurobiology of Neuropharmacological Basis of Reward (New York, NY: Claredon Press, 1989). opiate Abuse “ Trends in Pharmacological Sci- ence, 13:185 -;93, 1992. 18. O’Brien, C. P., Childress, A.R., McLelland.lan, A.T., et 8. Fischman, M.W,, and Mello, N.K. (eds.), NIDA al., “Classical Conditioning in Drug-Dependent Research Monograph #92: Testing for Abuse Humans,” P.W. Kalivas, and H.H. Samson (eds.), Liability of Drugs in Humans, U.S. Department of The Neurobiology of Drug and Alcohol Addiction, Health and Human Services Pub. No (ADM) Annals of the American Academy of Sciences 89-1613 (Washington, DC: U.S. Government 654:400415, 1992. Printing Office, 1989). 19. Post, R. M., Weiss, S.R.B., Fontana, D., et al., 9. Henningfield, J.E., Johnson, R.E., and Jasinski, “Conditioned Sensitization to the Psychomotor D. R., “Clinical Procedures for the Assessment of Stimulant Cocaine,” P.W. Kalivas, and H.H. Abuse Potential,” Methods of Assessing the Samson (eds.), The Neurobiology of Drug and Reinforcement Properties of Drugs, M.A, Bozarth Alcohol Addiction, Annals of the American Acad- (cd.) (Berlin: Springer-Verlag, 1987). emy of Sciences 654:386-399, 1992. 10. Jaffe, J.H., “Drug Addiction and Drug Abuse,” 20. Samson, H.H., and Harris, R.A., “Neurobiology The Pharmacological Basis of Therapeutics, A.G. of Alcohol Abuse,” Trends in Pharmacological Gilman, T.W. Rail, A.S. Nies, et al.(eds.) (New Science 13:206-211, 1992. York, NY: Pergammon Press, 1990). 21. Shippenberg, T. S., Herz, A,, and Spanagel, R., 11. Jasinski, D. R., and Henningfield, J.E., “Human “Conditioning of Opioid Reinforcement: Neu- Abuse Liability Assessment by Measurement of roanatomical and Neurochemical Substrates,” Subjective and Physiological Effects,” NIDA P.W. Kalivas, and H.H, Samson (eds.), The Research Monograph #92: Testing for Abuse Neurobiology of Drug and Alcohol Addictions, 18 I Biological Components of Substance Abuse and Addiction

Annals of the American Academy of Sciences nol Self-Administration,’ P.W. Kalivas, and H.H. 654:347-356, 1992. Samson (eds.), The Neurobiology of Drug and 22. Spyraki, C., Fibiger, H. C., and Phillips, A.G., Alcohol Addiction, Annals of the American Acad- “Attenuation of Heroin Reward in Rats by emy of Sciences 654:220-241, 1992. Disruption of the Mesolimbic Dopamine Sys- 26. Wikler, A., “Recent Progress in Research on the tem,” Psychopharmacology 79:278-283, 1983. Neurophysiological Basis of Morphine Addic- 23. Stewart, J., “Neurobiology of Conditioning to tion,” American Journal of Psychiatry 105:329- Drugs of Abuse,” P.W. Kalivas, and H.H. Samson 338, 1948. (eds.), The Neurobiology of Drug and Alcohol 27. Wise, R. A., “The Role of Reward Pathways in the Addiction, Annals of the American Academy of Development of Drug Dependence,” Pharmacolo- Sciences 654:335-346 , 1992. gical Therapeutics 35:227-263, 1987. 24. Vavrousek-Jakuba, E., Cohen, C.A., and Shoe- 28. Wise, R.A., Bauco, P., and Carlezon, W.A., maker, W.J., “Ethanol Effects of CNS Dopamine “Self-Stimulation and Drug Reward Mechanisms,” Receptors: In Vivo Binding Following Voluntary P.W. Kalivas, and H.H. Samson (eds.), The Ethanol Intake in Rats,” C.A. Narnajo, and E.M. Neurobiology of Drug and Alcohol Addiction, Sellers (eds.), Novel Pharmacological Interven- Annals of the American Academy of Sciences tions for Alcoholism (New York NY: Springer- 654:192-198, 1992. Verlag, 1990). 29. Woolverton, W. L., and Johnson, K. M., “Neurobi- 25. Weiss, F., Herd YL., Ungerstedt, U., et al., ology of Cocaine Abuse,” Trends in Pharmacol- “Neurochemica.1 Correlates of Cocaine and Etha- ogical Science 13:193-200, 1992. The Neuropharmacology of Drugs of Abuse 3

rugs of abuse interact with the neurochemical mechanisms of the brain. Some of these interactions are directly related to the reinforcing properties of a drug, while others are related to other effects associated with the drug. As in other areas of neuroscience, the level of understanding about these interactions and the mechanisms involved has increased tremendously over the last decade. The fundamentals of information processing in the brain and how psychoactive drugs can alter these processes are being elucidated. For drugs of abuse, certain commonalities have begun to emerge. While drugs of abuse have a wide range of specific individual actions in the brain, there is growing evidence that their reinforcing properties may result from a shared ability to interact with the brain’s reward system. For each drug of abuse, this action, coupled with its actions in other areas of the brain, contributes to the overall behavioral effect the drug produces. In some cases, the relationship of a drug’s neurochemical action and the behavioral effects it produces have been clearly elucidated, while in others much remains to be learned. This chapter describes how drugs of abuse affect neurochemical activity and the mechanisms that may underlie the characteristics contributing to and determining a drug’s abuse potential, namely, their reinforcing affects, the neuroadaptive responses associated with them, and the development of withdrawal symptoms. A brief summary of basic neuropharmacology is provided to give general background information on how drugs work in the brain. ,0 I

19 20 | Biological Components of Substance Abuse and Addiction

NEUROPHARMACOLOGY Figure 3-l—The Synapse and Associated Neurons are the cells that process information Structures in the brain. Neurotransmitters are chemicals released by neurons to communicate with other neurons. When a neuron is activated it releases a Nerve impulse neurotransmitter into the synapse, the gap between two neurons (see figure 3-l). The molecules of the neurotransmitter move across the synapse and attach, or bind, to proteins, called receptors in the outer membrane of an adjacent M( cell. Once a neurotransmitter activates a receptor, it unbinds from the receptor and is removed from the synapse. This is done either by the neurotrans- v mitter being taken back up into the neuron that released it (a process called reuptake) or by being chemically broken down. Usually the axon terminal is the part of the neuron that releases neurotransmitters into the synapse, and the den- drites and cell body are the areas of the neuron Neurotransmitters Receptors that contain receptors that form synapses with the Receiving cell axons of other neurons. SOURCE: Office of Technology Assessment, 1993. For each neurotransmitter in the brain, there are specific receptors to which it can attach. Binding a receptor for one neurotransmitter can affect a by the neurotransmitter activates the receptor, receptor for another neurotransmitter. In such which can have different effects depending on the case, the receptors are biochemically coupled: the receptor. Receptors can be linked to a variety of activation of one modulates the function of the membrane and cellular mechanisms that are other, either increasing or decreasing its activity. turned on or off by the activation of the receptor. A neuron can also have receptors for the neuro- Some receptors open or close ion channels (i.e., transmitter it releases; these are usually located for charged molecules such as potassium, sodium, near the site where the neurotransmitter is re- calcium, or chloride) in the membrane of the cell. leased into the synapse. Such receptors are acted These channels regulate the flow of ions in and on by the neuron’s own neurotransmitter to out of the cell. The relative concentration of ions regulate the release of the neurotransmitter. Thus, between the inside and outside of a neuron is these autoreceptors, as they are called, act as a crucial in the activity of the neuron. Other feedback mechanism to regulate a neuron’s activ- receptors activate or inhibit intracellular mecha- ity. The activity of a neuron will be determined by nisms called second messengers. There are a the cumulative activity of all of its various number of different second messengers that receptors. Activation of a neuron generates an control various aspects of cellular activity. electrical impulse inside the neuron that travels A neuron can have thousands of receptors for from the cell body, down the axon, to the axon several different neurotransmitters. Some neuro- terminal, where the impulse causes the release of transmitters activate neurons (excitatory neuro- neurotransmitter into the synapse. transmitters), while others decrease neuronal While receptors are specific for a neurotrans- activity (inhibitory neurotransmitters). Sometimes rnitter, there may be a variety of receptor sub- Chapter 3-The Neuropharmacology of Drugs of Abuse I 21

types, linked to different cellular mechanisms, brain. As a result, effects are felt within 5 to 10 that all respond to the same neurotransmitter. In seconds, making inhalation the fastest route of this way one neurotransmitter can have diverse administration. The route of administration of a effects in different areas of the brain. In addition, drug can determine the potency and efficacy the neurons are connected to different circuits in the drug will have on affecting brain activity. In some brain, further accounting for diverse effects. cases, the route of administration can also con- Many chemicals have been identified as neuro- tribute to the abuse potential of a drug. transmitters, among them dopamine, norepinephrine, serotonin, acetylcholine, various amino acids, DRUGS OF ABUSE and peptides. As discussed in chapter 2, some of these are of particular relevance to the rewarding I Stimulants properties of drugs of abuse. As the name implies, stimulant drugs have an Psychoactive drugs alter these normal neuro- energizing effect that promotes an increase in chemical processes. This can occur at any level of psychological and/or motor activity. Stimulants activity including mimicking the action of a such as cocaine and the amphetamines have their neurotransmitter, altering the activity of a recep- most pronounced effect on the monoamine neuro- tor, acting on the activation of second messen- transmitters (i.e., dopamine, serotonin, norep- gers, or directly affecting intracellular processes inephrine, and epenephrine) in the brain. They that control normal neuron functioning. also stimulate the physiological mechanisms that In order to have these affects, a drug must enter are triggered in stressful situations (the ‘‘fight or the brain, by diffusing from the circulatory system flight” response) via activation of the sympa- into the brain. Routes of administration refers to thetic nervous system. These include increases in the methods used to deliver a drug into the heart rate and blood pressure and the release of bloodstream. The route of administration affects various hormones. The arousing and euphoric how quickly a drug reaches the brain. In addition, effects associated with these drugs are associated the chemical structure of a drug plays an impor- with these various actions. Other stimulant drugs tant role in the ability of a drug to cross from the are caffeine and nicotine. These drugs have circulatory system into the brain. The four main various mechanisms of action, but their net effect routes of administration for drugs of abuse are is to stimulate central nervous system (CNS) oral, nasal, intravenous, and inhalation. With oral activity. ingestion, the drug must be absorbed by the stomach or gut, which usually results in a delay COCAINE before effects become apparent, and must pass Cocaine is found in the leaves of the Erythrox- through the liver where it can be chemically ylon coca plant, a large shrub indigenous to South broken down. Using the nasal route, effects are America. The compound is extracted from the usually felt within 1 to 3 minutes, as the capillary leaves and is then processed into either paste, rich mucous membranes of the nose rapidly powder, or freebase form. The paste is the most absorb substances into the bloodstream. Intrave- rudimentary, unrefined form. Additional process- nous administration produces effects in 1/2 to 2 ing of the paste by adding hydrochloric acid minutes and is slowed only by detour back produces cocaine powder (cocaine hydrochlo- through the lungs that venous blood must take to ride). Cocaine powder is often administered via reach the brain. Lastly, the inhalation method nasal insufflation (i.e., snorting). Freebase co- bypasses the venous system because the drug is caine is the pure cocaine base released from absorbed into the arterial blood flow, which goes cocaine hydrochloride by further separation using directly from the lungs to the heart and then to the simple chemicals such as ether or sodium hydrox- 22 I Biological Components of Substance Abuse and Addiction

ide. This freebase cocaine is easily absorbed into rnine has a number of receptor subtypes distrib- the membranes of the relatively alkaline environ- uted in different brain areas. The reinforcing ment of the body. The well-known “crack” properties of cocaine are mediated via dopamine cocaine is simply baking soda and water mixed activation of at least two of these, the DI and D2 with the base to create a solid form of freebase dopamine receptor subtypes (39,62), and more cocaine which is immediately and completely recently there is evidence for an action at D3 re- absorbed by the body when smoked. The most ceptors (12). The increase in dopamine activity common routes of administration for cocaine are via D2 and D1 receptors is also important in the smoking and snorting although the intravenous other behavioral effects of cocaine (62). The role route is also used and is often preferred by those of cocaine’s actions on brain norepinephrine and who also inject other drugs, such as opiates (45). serotonin uptake in its behavioral effects has not In humans, cocaine produces an elevation in been clearly established (62). mood and a sense of increased energy and Chronic administration-Chronic adminis- alertness. This can include an improvement in tration of cocaine activates a number of brain concentration and attention, a reduction in the neurochemical compensatory mechanisms, the sense of fatigue and performance decrement details of which are not completely understood. caused by sleep deprivation, appetite suppression, Both short- and long-term changes in the dynam- and an increase in libido. The toxic effects of high ics of neurotransmission following repeated co- doses of cocaine include delirium, seizures, caine administration have been observed in ex- stupor, cardiac arrhythmias, and coma. Seizures periments. Results from animal studies indicate can result in sustained convulsions that stop that continued administration results in a sus- breathing. tained increase in dopamine levels within the Acute administration—The most prominent synapses of the nucleus accumbens (60). This is pharmacological effect of cocaine is to block the believed to be due to a decreased sensitivity of reuptake of dopamine back into the presynaptic dopamine autoreceptors, which regulate the re- terminal once it has been released from a neuron lease of dopamine from the presynaptic terminal. terminal (61), resulting in increased levels of In their normal state, these autoreceptors decrease dopamine at its synapses in the brain (see figure the amount of dopamine released into the syn- 3-2). The specific uptake site for dopamine has apse. Changes also seem to occur in the number been identified and cocaine’s actions on the of postsynaptic receptors for dopamine, but the mechanism that transports dopamine back into exact nature of these changes has yet to be the neuron is an active area of research. Within the characterized. Both increases and decreases in brain mesocorticolimbic pathway (MCLP), levels receptor numbers have been reported (62). The of dopamine increase in the synapses between the exact effects of chronic cocaine administration terminals of the neurons projecting from the seem to vary among receptor subtypes and ventral tegmental area and the neurons in the locations. nucleus accumbens and medial prefrontal cortex A number of changes in the intracellular (60,62). In addition to blocking dopamine reup- mechanisms, including second messenger sys- take, cocaine also blocks the reuptake of norep- tems, involved in the activity of dopamine inephrine and serotonin (62). neurons in the ventral tegmental area and nucleus The acute behavioral effects of cocaine are the accumbens have been described following chronic result of these neurochemical actions. The acute cocaine administration (10). The changes are reinforcing properties of cocaine are due to its thought to be due to alterations in the expression capacity to enhance the activity of dopamine in of the genes that regulate and control the intracel- MCLP. As with most neurotransmitters, dopa- lular mechanisms. The net effect of these changes — ..-

Chapter 3-The Neuropharmacology of Drugs of Abuse | 23

Figure 3-2-Cocaine’s Principal Action Mechanism These changes may result from alterations in dopamine transmission that effect other areas of the brain. These secondary responses indicate that the neurochemical adaptive response to repetitive cocaine administration involves a complex inter- Dopamine terminal action between multiple neuronal pathways and neurotransmitter systems (62). \ Matching the pharmacological profile, the behavioral response to repeated cocaine administration is also complex. Results from animal studies suggest that how the drug is administered can affect whether sensitization or tolerance occurs. Intermittent administration of cocaine can trigger sensitization to some of its specific motor effects, such as stimulating levels of activity (61,62). Conversely, tolerance to these motor effects develops when the drug is given continu- ously (62). While it is unclear whether tolerance develops to cocaine’s reinforcing effects, experimental evidence suggests that it does and subjec-

Cooaine’s principal mechanism of action is to block the uptake tive reports from cocaine users that the euphoric of dopamine into the presynaptic terminal. (Compare to figure actions of the drug diminish with repeated use 3-l.) support the notion (45,62). Increasingly, experi- SOURCE: Office of Technology Assessment, 1993. mental evidence suggests that chronic cocaine administration increases drug craving (36,42). is to reduce the capacity of ventral tegmental A withdrawal reaction occurs with the abrupt neurons to transmit dopamine signals to the cessation of cocaine administration after repeated neurons in the nucleus accumbens. This could use. This reaction is marked by prolonged sleep, represent a mechanism by which tolerance to the depression, lassitude, increased appetite, and rewarding properties of cocaine could develop craving for the drug (61). In animal studies, and could contribute to cocaine craving. Impor- cocaine withdrawal results in an increase in the tantly, these changes are lacking in other dopam- level of electrical stimulation necessary to induce ine pathways not involved in drug reward. Similar a rat to self-stimulate the brain reward system changes were observed following chronic mor- (40). This indicates that during cocaine with- phine administration . These findings suggest that drawal, the brain reward system is less sensitive. a common physiological response to chronic While the precise pharmacological mechanism administration of these drugs of abuse may exist. underlying this withdrawal is unknown, it is Further investigations are necessary to com- suspected that it relates to some hypoactivity in pletely characterize the changes that occur and to dopamine functioning within the brain reward determine whether they are typical for other drugs system (40). Changes in the expression of genes of abuse. that control intracellular mechanisms (10) repre- Finally, animal studies have shown that re- sent a possible mechanism that could account for peated administration of cocaine causes changes this change and could contribute to the drug in the levels of other neurotransmitters, most craving associated with chronic cocaine use. notably some of the peptide neurotransmitters. Avoidance of the withdrawal reaction can be 24 | Biological Components of Substance Abuse and Addiction

another important determinant in continued co- Figure 3-3-Amphetamines’ Principal caine use. Action Mechanism

AMPHETAMINES r ‘- 77- ” - ” - Amphetamines (i.e., dextroamphetamine, meth- amphetamine, phemetrazine) produce effects sim- Nerve Impulse ilar to cocaine (20). Amphetamine users describe the euphoric effects of the drug in terms indistinguishable from those used by cocaine users and in \ Amphetamines the laboratory, subjects cannot distinguish be- ‘\ tween the subjective effects of cocaine and \ $ /“ amphetamine (36). This is not to suggest that P b \, cocaine and amphetamine have identical mecha- ■ ■ ■ nisms of action or that under properly selected experimental conditions differences between their effects cannot be demonstrated. For example, cocaine effects are relatively brief after intravenous injection, whereas those of methampheta- mine may last for hours (36). Oral ingestion is the most common route of administration of ampheta- I mines, although intravenous injection, smoking, and nasal insufflation are also used. Amphetamines’ principal mechanismism of action is to stimulate the release of dopamine from the presynaptic terminal. Acute administration—Like cocaine, acute (Compare to figure 3-1.) amphetamine administration results in mood SOURCE: Office of Technology Assessment, 1993. elevation and increased energy. In addition, the user may experience feelings of markedly enhanced physical strength and mental capacity. dopamine reuptake following normal release of Amphetamines also stimulate the sympathetic the transmitter from the terminal, the ampheta- nervous system and produce the physiological mine increase in dopamine activity is independ- effects associated with sympathetic activation. ent of neuronal activity (61). As a result of this High doses of amphetamine produce a toxic difference, amphetamines are more potent than syndrome that is characterized by visual, audi- cocaine in increasing the levels of dopamine in tory, and sometimes tactile hallucinations. There the synapse. Amphetamines also directly stimu- are also feelings of paranoia and disruption of late the release of norepinephrine, epinephrine, normal thought processes. The toxic reaction to and serotonin from neurons. Among the ampheta- amphetarnines is often indistinguishable from an mines, the balance between their actions on these episode of the mental disorder schizophrenia. different neurotransmitter systems vary. For Not surprisingly, action of amphetamines is example, methylenedioxymethamphetamine similar to cocaine. The reinforcing properties of MDMA) has a particularly potent effect on the these drugs is due to their ability to enhance serotonin system, which imbues this drug with a dopamine action in MCLP. However, while psychedelic effect. amphetamines also block dopamine reuptake, Chronic administration—As with cocaine, their most significant action is to directly stimu- both sensitization and tolerance to different ef- late the release of dopamine from neurons (61) fects of amphetamines occur. Animal studies (figure 3-3). Thus, unlike cocaine, which blocks have shown that intermittent administration of Chapter &The Neuropharmacology of Drugs of Abuse | 25

amphetaminees results in sensitization to the there is great individual variability in caffeine’s motor stimulating effects (61). This sensitization effects (49). These differences are linked to is thought to be due to an augmentation of differences in rates of caffeine absorption from dopamine release after intermittent, repeated drug the gastrointestinal system and metabolism in the administration. Tolerance to the euphoric effects body. Age also seems to affect the response to of amphetamine develops after prolonged, contin- caffeine, in that older people show an increased uous use (45). Such tolerance is believed to be sensitivity to caffeine’s stimulating effects (49). caused by depletion of stored neurotransmitters, This is particularly true of caffeine’s disruptive especially dopamine, in the presynaptic terminals effects on sleep. as a result of the continued stimulation of release Acute administration-caffeine exhibits, at from the stores by the drug. Drug craving is most, weak reinforcing effects in animal self- increased with continued amphetamine use (36,42). administration experiments (28,33). The level of Finally, a withdrawal syndrome, similar to co- responding induced by caffeine is much less than caine’s, is produced with the cessation of amphet- that seen with other stimulants such as ampheta- amine administration after prolonged use. mine and cocaine (33). In humans, experiments demonstrate that caffeine’s reinforcing actions CAFFEINE are also minimal and dose-dependent (28,33). Caffeine is the most widely used psychoactive Low doses are mildly reinforcing with subjects substance in the world (28,33). Surveys indicate reporting positive subjective effects, while higher that 92 to 98 percent of adults in North America doses produce adverse effects. The results from regularly consume caffeine, mostly in coffee or human studies indicate that reinforcement occurs tea (28). Caffeine belongs to a class of compounds only under certain conditions and not across all called methylxanthines, which act as CNS stimu- individuals (28). The mechanism of caffeine’s lants (49). The stimulating effects of caffeine are reinforcing actions is unknown. due to its ability to block the receptors for the Chronic administration—Humans can de- inhibitory neurotransmitter adenosine (49). Caf- velop tolerance to many of the physical manifes- feine blocks both the Al and A2 adenosine tations of caffeine’s actions such as increased receptor subtypes, having its more potent effect heart rate and higher blood pressure and there is on the A 1 receptor (49). Adenosine inhibits the evidence that tolerance develops to its behavioral release of various neurotransmitters, in particular consequences including alertness and wakeful- the excitatory amino acid glutamate. Therefore, ness (28,33,49). In animals, tolerance develops to caffeine blockade of adenosine receptors results some of caffeine’s behavioral effects such as the in increased glutamate activity. Caffeine also stimulation of locomotor activity (49). increases the levels of norepinephrine and sero- A withdrawal syndrome has clearly and repeat- tonin, which contributes to the drug’s CNS edly been demonstrated after the cessation of stimulating effects (49). Caffeine’s effects on chronic caffeine consumption (28,33,49). Changes dopamine are unclear in that increases, decreases, in mood and behavior can occur with lethargy and or no change in the release of dopamine have been observed following caffeine administration in headache being the two most common symptoms various experiments (49). of caffeine withdrawal (28). These changes may In humans, caffeine has a general alerting be the result of a compensatory increase in affect, and it has been shown to increase locomo- adenosine receptors resulting from the chronic tor activity in laboratory animals (49). However, blockade by caffeine. However, more studies are experimental evidence indicates that in humans needed to confirm this possibility (49). 26 | Biological Components of Substance Abuse and Addiction

NICOTINE dopamine release is modest, and as a result, It is generally accepted that while people nicotine is a comparatively weak reinforcer in smoke tobacco for many reasons (e.g., social, animal experiments (4,56). Nonetheless, nicotine cultural), the majority of people who smoke reinforcing properties are thought to be the result tobacco do so in order to experience the psy- of this action.Animal “ study results indicate that choactive properties of the nicotine contained in activation of nicotine receptors also stimulates the smoke (4,56). Furthermore, a significant the release of noradrenaline from neurons in the proportion of habitual smokers become depend- locus ceruleus and may reduce serotonin activity ent on nicotine and tobacco smoking has all the in the hippocampus (4). However, the exact attributes of drug use considered to be addicting nature of these changes and the role they may play (4,38). Nicotine activates one of the receptor in the behavioral effects of nicotine is unclear. subtypes for the neurotransmitter acetylcholine Chronic administration—Tolerance devel- (38,56). As a result, this receptor is called the ops to many of the effects of nicotine and a nicotine receptor. The psychological effects of withdrawal syndrome marked by irritability, anx- nicotine are fairly subtle and include mood iety, restlessness, and difficulty in concentrating changes, stress reduction, and some performance develops when tobacco use stops (4,36,45). In enhancement (7). addition, a craving for tobacco, which may When tobacco is smoked, nicotine is readily subside in a few days, occurs (36). The pharma- absorbed by the lungs. Studies of smoking cological mechanisms underlying these changes patterns have shown that habitual smokers tend to are unknown. Although animal studies have smoke more efficiently, because they inhale suggested that chronic administration of nicotine longer, have shorter intervals between puffs, and increases the number of nicotine receptors, the take a greater number of puffs per cigarette thus mechanism that mediates this increase and the increasing the dose of nicotine they receive (38). possible involvement it plays in the tolerance and Smokeless tobacco involves either chewing to- withdrawal associated with nicotine remains to be bacco leaves or placing tobacco between the clarified (4,56). cheek and gums. The blood nicotine level achieved using smokeless tobacco can be comparable to that achieved by smoking cigarettes. Because of | Phencyclidine the route of administration, however, blood nico- Phencyclidine (PCP) is representative of a tine levels remain higher longer (45). Evidence unique class of abused drugs that includes the indicates that the diseases related to the use of anesthetic ketamine and other drugs similar to tobacco may be caused by different constituents PCP. PCP was developed as an injectable anes- of tobacco or tobacco smoke. For example, thetic in the 1950s. However, PCP anesthesia is cardiovascular effects are related to carbon mon- quite dissimilar to that produced by typical oxide in the smoke, and the effects on the heart general anesthetics (6,8). It produces a dissocia- and various cancers are probably due to carcino- tive state in which patients are generally unre- gens in the tobacco (36). sponsive and perceive no pain. Patients are Acute administration—Nicotine stimulates amnesic for the surgery and CNS depression seen the release of dopamine from dopamine neurons with other general anesthetics is absent. Delirium in the MCLP (4,56). This results from activation that often occurs on emergence from PCP anes- of nicotine receptors that stimulate activity in thesia curtailed PCP’s use as an anesthetic in dopamine neurons in the ventral tegmental area. humans. It is still sometimes used as a veterinary However, when compared to the effects of anesthetic but is no longer marketed in the United cocaine or amphetamine, the nicotine increase in States. Chapter 3-The Neuropharmacology of Drugs of Abuse | 27

At nonaesthetic doses PCP produces behav- (6,13). From clinical reports of human PCP use ioral effects in common with several other drugs and from animal studies, route of administration including amphetamines, barbiturates, opiates, appears to affect the self-administration rate. and psychedelics (13). Given its wide range of Intravenously delivered PCP has been established behavioral effects, PCP’S broad neurochemical as a reinforcer in rats, dogs, and primates. Oral action in the brain is not surprising. PCP antago- PCP is rapidly established as a reinforcer in nizes the actions of the excitatory amino acid primates but not in rats (13). In humans, the most neurotransmitter glutamate at the N-methyl-D- common route of administration of PCP is aspartate (NMDA) receptor, one of the receptor smoking. subtypes for glutamate (8,37). Glutamate is found The mechanism of action of PCP’S reinforcing throughout the brain and increases the flow of effects are unclear. Part of PCP’S behavioral calcium ions into cells to cause excitatory actions. effects are similar to dopamine-stimulating drugs The NMDA receptor controls the calcium ion like amphetamine (37) and its administration channel acted on by glutamate and binding of potentates the sedating properties of alcohol and PCP to the receptor blocks calcium entry into the barbiturates (6,13). As previously mentioned, cell. It is likely that the diverse behavioral effects PCP blocks the action of glutamate at the NMDA of PCP are due to the fact that glutamate is widely receptor. All of these actions may be relevant to distributed in the brain and regulates the activity the production of its reinforcing effects. of a number of other neurotransmitter systems. Chronic administration—Repeated PCP ad- PCP also affects brain dopamine systems in ways ministration has been shown to produce tolerance similar to amphetamine (37). to many of its effects in animals (6,13). The The subjective effects of PCP administration magnitude of the tolerance, however, is less than can vary dramatically depending on a user’s what is seen with most other drugs of abuse (13). personality and a user may experience vastly Systematic studies of PCP tolerance in humans different reactions during different drug-taking have been few, but chronic PCP users report that episodes (13). In most cases, low doses produce after regular use they increase the amount of PCP euphoria, feelings of unreality, distortions of smoked by at least twice (13). Some evidence time, space, and body image, and cognitive from animal studies also suggests that sensitiza- impairment. Higher doses produce restlessness, tion may develop to PCP under certain conditions panic, disorientation, paranoia, and fear of death. (13). As with its use as an anesthetic, PCP often causes A withdrawal syndrome occurs in animals that amnesia to occur beginning immediately after the have been chronically administered PCP (13). It drug is taken until its effects begin to wear off. is characterized by signs of CNS hyperexcitabil- PCP is often associated with violent behavior in ity such as twitches, tremors, and increased users but laboratory studies indicate that it does susceptibility to seizures. Although PCP with- not increase aggressive behavior in animals (6). In drawal syndrome can be reliably produced in fact, the bulk of evidence indicates that PCP animals, a withdrawal syndrome in humans has decreases aggression at most doses under most yet to be clearly identified (13). Symptoms of experimental conditions (6). The violence often depression, drug craving, increased appetite, and associated with PCP use is likely to be due to a increased need for sleep have been reported to combination of its multiple effects including its occur between 1 week and 1 month after termina- ability to block pain and its stimulant and tion of chronic PCP use (57). The lack of clear psychedelic actions. evidence of a PCP withdrawal syndrome in Acute administration—In animal studies, PCP humans may be due to the fact that the drug is has been shown to be a highly effective reinforcer usually not taken in large enough quantities 28 I Biological Components of Substance Abuse and Addiction

and/or not frequently enough to produce symp- effects. A similar spectrum of effects is seen with toms (13). barbiturates and benzodiazepines. The neurochemical mechanisms underlying Acute administration—In humans, acute con- PCP tolerance and withdrawal are unknown. sumption of alcohol produces a sense of well Both, direct PCP-induced alterations in NMDA being and mild euphoria and studies have shown receptors and secondary changes in other neuro- that animals will orally self-administer alcohol. transmitter systems as a result of altered gluta- Several lines of evidence have implicated dopam- mate activity could play a role. ine, serotonin, GABA, and opioid peptides in alcohol reinforcement. | Sedatives Results from several types of studies indicate Alcohol, barbiturates, and benzodiazepines are that dopamine is involved in the acute reinforcing drugs that inhibit CNS activity. Many of the abuse effects of alcohol. Drugs that block the activity of inhalants appear to produce similar effects to dopamine reduce alcohol self-administraticm in these sedative/depressant drugs. Although all rats (40,53). Also, depending on the dose, alcohol these drugs have different specific mechanisms may stimulate locomotor activity and produce an of action in the brain, they all share the ability increase in dopamine levels in the nucleus accum- to enhance the activity of the inhibitory amino bens (60). Finally, data from genetic models of acid neurotransmitter gamma amino butyric acid alcohol preference, in which a strain of rats is bred (GABA). In some cases activation of inhibitory to have a higher than normal preference for pathways in the brain, in turn, hampers other self-administering alcohol, indicate that alcohol- inhibitory pathways. The effect of inhibiting an induced release of dopamine is higher in the inhibitory pathway is often the net activation of a alcohol-preferring rats than in nonpreferring rats brain region. This mechanism of interfering with (60). These data suggest that activation of the other inhibitory pathways is thought to play a role MCLP is involved in the reinforcing actions of in the abuse potential of these drugs. alcohol. However, the precise mechanisms of this activation are unclear. ALCOHOL Alcohol also is thought to enhance GABA Alcohol differs from most other drugs of abuse activity in specific parts of the brain. GABA in that it has no known receptor system in the enhancement has been linked to the reinforcing brain (52). Alcohol affects a number of different effects of alcohol by the observation that drugs neurotransmitter systems through its action on the that block GABA activity also decrease alcohol membranes of neurons and the ion channels, intake in alcohol-preferring rats, while drugs that particularly those for calcium and chloride, that increase GABA activity act as a surrogate for lie within them (43). In general, alcohol inhibits alcohol, maintaining alcohol preference during receptors for excitatory neurotransmitters and alcohol withdrawal (27). In addition, an increase augments activity at receptors for inhibitory in the number of GABA containing fibers has neurotransrnitters (52). For example, alcohol been observed in the nucleus accumbens of enhances the activity of GABA by affecting ion alcohol-preferring rats as compared with non- channels that are related to a subpopulation of the preferring rats (34). Part of alcohol’s reinforcing

GABAA receptor subtype (figure 3-4) and de- effects possibly are due to an increase of GABA creases the action of the excitatory amino acid inhibition on other inhibitory neurons that de- neurotransmitter glutamate, through inhibition of crease the activity of the dopamine neurons in the the NMDA receptor (43,52,55). The net effect of ventral tegmental area. This chain of action would alcohol is to depress activity in the brain produc- have the ultimate effect of increasing the activity ing its characteristic sedating and intoxicating of the dopamine neurons (27). However, the Chapter &The Neuropharmacology of Drugs of Abuse | 29

Figure 3-4-The GABAA Receptor Complex ulation decreased alcohol consumption (40). Thus, while serotonin seems to be involved in alcohol’s acute reinforcing effects the exact mechanisms that may be involved still need to be clarified. The discrepancies observed in experiments may ultimately be explained by differential effects of alcohol on serotonin receptor subtypes in various brain regions. In animal studies alcohol self-administration is decreased by drugs that block the action of the opioid peptide neurotransmitters and is enhanced by drugs that mimic their action, suggesting a role for these neurotransmitters in alcohol reinforce- Cell membrane ment (40). However, drugs that block opioid peptide activity also suppress food and water

Inside the cell intake indicating that their action is not specific ‘-’4 for alcohol but is related to an inhibition of consummatory behavior in general (40). Never- The GABAA receptor complex is made up of a chloride ion channel surrounded by a GABA receptor (GABA) and a theless, as a result of this experimental work benzodiazepine receptor (BDZ). Activation of the GABA A naltrexone, an opioid peptide blocking drug, has receptor complex increases the flow of chloride into a cell, thereby inhibiting the activity of the cell. been tested in alcohol dependent humans, where SOURCE: Office of Technology Assessment, 1993. it has been demonstrated to be a promising adjunct to behavioral relapse prevention treat- experimental evidence supporting this idea is ment (50,59). equivocal (27). While it is clear that both GABA Chronic administration—Repeated adminis- and dopamine are involved in the reinforcing tration of alcohol results in tolerance to many of affects of alcohol, the relationship between these its effects. Tolerance to the motor, sedative, systems in this action is yet to be defined (27). antianxiety, and anesthetic effects of alcohol has Some experimental evidence implicates sero- been shown in animal studies and tolerance in tonin in the reinforcing effects of alcohol, al- humans is indicated by the fact that dependent individuals increase their consumption over time. though that involvement is not as clear as for How alcohol tolerance develops is not clearly dopamine and GABA. Alcohol-preferring rats understood, but since alcohol affects the activity show a relative deficit in brain serotonin levels as in a wide range of neurotransrnitter systems, it compared to nonpreferring rats (48) and evidence may involve mechanisms common to many or all suggests that alcoholic patients have lower levels of them. In particular, an adaptation in membrane of serotonin than nonalcoholics (5). In animal channels for the calcium ion following chronic studies, drugs or experimental manipulations that exposure to alcohol may play a significant role in increase the levels of serotonin in the brain reduce alcohol tolerance (43). Dispositional tolerance voluntary intake of alcohol (40). These results also plays a role. would seem to indicate that part of the reinforcing Alcohol withdrawal in animals is characterized effects of alcohol is due to its inhibitory effect on by CNS hyperexcitability. In humans this hyper- the serotonin system. However, a variety of excitability results in anxiety, anorexia, insomnia, studies using animals with experimentally de- tremor, disorientation, and sometimes hallucina- pleted serotonin levels has found that this manip- tions. In severe withdrawal a syndrome called 30 I Biological Components of Substance Abuse and Addiction

delirium tremens, marked by vivid hallucinations, GABA, the GABAAreceptor (see figure 3-4). The disorientation with respect to time and place, and GABAA receptor is linked to a chloride ion outbursts of irrational behavior, may develop. channel. Stimulation of the receptor by GABA In humans, the craving for alcohol during opens the channel and increases the flow of periods of abstinence has often been considered a chloride into the neuron, which acts to inhibit the prime factor underlying excessive alcohol use. cell’s activity. Barbiturates increase the amount However, there is no evidence of a correlation of time the chloride channel stays open thus between development of physical dependence increasing the inhibitory effects of GABA. and a specific craving for alcohol in experimental Acute administration—The reinforcing prop- . animals (52). This same result has been noted in erties of barbiturates have been clearly demon- human alcoholics in an experimental laboratory strated in both animal and human studies (46). . situation (44). While avoidance of withdrawal Animals readily self-administer barbiturates in a symptoms plays a role in continued alcohol use in variety of different experimental paradigms. In humans, the relationship between the develop- humans, studies using self-report measures have ment of the withdrawal syndrome and alcohol demonstrated that drug-experienced subjects, blind craving during abstinence needs to be clarified to the identity of the drug, consistently give (52). barbiturates high rankings when asked to rate a The CNS hyperexcitability associated with series of drugs as to ‘liking” or ‘would you take alcohol withdrawal is thought to be related to this drug again?” Also, in controlled studies, alcohol-induced alterations in the sensitivity of human subjects will work to receive barbiturates GABA and glutamate receptors (40,43). Experi- and will do more work to receive the drug if the mental evidence indicates that prolonged alcohol available dosage is increased (46). The mecha- exposure decreases the sensitivity of GABA nism of barbiturate reward is unclear. Since one receptors (47) and increases the sensitivity of of its major effects is to enhance GABA activity, glutamate receptors (24). With the cessation of barbiturates, like alcohol, may increase GABA alcohol intake, these changes are manifested inhibition of other inhibitory neurons that de- throughout the brain as a decrease in the overall crease the activity of the dopamine neurons in the activity of the inhibitory neurotransmitter GABA ventral tegmental area. Further studies are neces- and an increase in the activity of the excitatory sary to confirm this possibility. amino acid neurotransmitter glutamate. Chronic administration—With continued use some tolerance develops to most effects of the BARBITURATES barbiturates (46). Little tolerance develops to the Barbiturates are a class of drugs that depress lethal dose. Unlike most other drugs of abuse, CNS activity. First introduced in the early 1900s, both dispositional and phaxmacodynamic toler- barbiturates were widely prescribed as antianxi- ance are important in the development of barbitu- ety agents and sleep aids, and to treat other rate tolerance. Barbiturate withdrawal is marked psychiatric conditions. However, their lethal over- by a severe and sometimes life-threatening with- dose potential and high abuse potential, coupled drawal syndrome (46). Both anxiety and depres- with the advent of the safer benzodiazepine sion are common features, and with heavy, compounds curtailed their use starting in the prolonged use, the development of severe grand 1960s (46). mal tonic epileptic seizures can occur. The Barbiturates’ sedative effects result from their neurochemical changes responsible for the phar- ability to increase GABA activity (54). Their macodynamic tolerance and withdrawal syn- mechanism of action is through an augmentation drome have yet to be clearly established. Some of the activity of one of the receptor subtypes for experimental evidence suggests that tolerance is Chapter &The Neuropharmacology of Drugs of Abuse | 31

the result of the GABAA receptors becoming less animal studies (46). In humans, self-report stud- sensitive to the effects of barbiturates (54). With ies, similar to those used to examine barbiturates, drug cessation, the barbiturate stimulation of have demonstrated that benzodiazepines yield GABA activity ceases and the action of the modest rankings of liking and that given a choice, desensitized receptors manifests itself as an subjects consistently prefer barbiturates over overall decrease in GABA activity, resulting in benzodiazepines (25,46), Since benzodiazepines withdrawal symptoms. Again, the hyperexcitabil- act selectively on GABA activity it is probable ity that results is similar to what occurs in alcohol that their mild reinforcing properties are due to withdrawal. activation of GABA mechanisms similar to those described for alcohol. BENZODIAZEPINES Chronic administration—Prolonged expo- Benzodiazepines are a class of drugs intro- sure to benzodiazepines results in tolerance to duced in the 1960s as antianxiety agents (25). their therapeutic and other effects (19,21). This They rapidly replaced barbiturates, which have tolerance maybe due to a reduction in the significant abuse potential, to treat anxiety and functional activity of GABA as a result of a other psychiatric conditions, Like barbiturates, desensitization of the benzodiazepine receptor benzodiazepines have a general inhibitory effect caused by prolonged exposure to the drug (2 1). As in the brain by enhancing GABA activity. But with alcohol and barbiturates, a withdrawal syn- unlike barbiturates’ nonspecific effect on chloride drome occurs following benzodiazepine drug ion channels, benzodiazepines act by binding to cessation due to a decrease in GABA activity. In a specific benzodiazepine receptor (21,54). The general, the characteristics of benzodiazepine presence of a benzodiazepine receptor in the brain withdrawal are similar to barbiturate withdrawal, indicates the presence of a naturally occurring but at typical benzodiazepine therapeutic doses endogenous neurotransmitter that normally inter- the magnitude of the symptoms are less severe acts with the receptor. An endogenous benzodiazepine- than seen in barbiturate withdrawal. Nonetheless, like neurotransmitter has yet to be identified. since benzodiazepines are widely prescribed, The benzodiazepine receptor is coupled with their ability to induce physical dependence at the GABAA receptor (figure 3-4). Stimulation of therapeutic doses indicates that care must be the benzodiazepine receptor increases the fre- given in their administration (25). quency of chloride ion channel opening in re-

sponse to GABA binding to the GABAA receptor (21). Also, benzodiazepines enhance the binding | Opiates of GABA to its receptor and the presence of The poppy plant, Papaver somniferum, is the GABA enhances benzodiazepine binding. The source of naturally occurring opium. This natural net affect of benzodiazepines is to augment substance contains more than 20 alkaloid com-

GABA activity at the GABAA receptor and pounds, including the drugs commonly known as enhance GABA action, The antianxiety and other morphine and codeine. Illicit drugs such as heroin sedative effects of the benzodiazepines are due to and other semisynthetic opiates are derived by this action. altering morphine (20). Opiates are drugs, natural Acute administration—Most benzodiazepi- or synthetic, which have opium- or morphine-like nes support only modest levels of self- activity. These drugs, when administered into the administration, much below the levels observed body, mimic the body’s endogenous, or self- with barbiturates, when given intravenously in produced, opioid peptide neurotransmitters (en- animal studies (25,46). When given orally, benzo- dorphins, enkephalins, and dynorphins). The diazepines do not induce self-administration in opioid peptide neurotransmitters are involved in 32 | Biological Components of Substance Abuse and Addiction

three major functions: modulation of pain percep- dopamine-dependent mechanism of opiate rein- tion and response to painful stimuli; reward; and forcement, there appears to be another component regulation of homeostatic functions such as food, not involving dopamine (40,41). This second water, and temperature regulation (39). The component is thought to involve opiate activity main types of opioid receptors have been identi- on the neurons of the nucleus accumbens and their fied in the brain— mu, delta, and kappa (18), all connections to other areas in the front of the ‘brain of which are linked to second messengers in the (41). cell (14). In general, the opioid peptide neuro- Chronic administration—In general, repeated transmitters have an inhibitory effect on the administration of opiates results in the develop- activation of neurons (18). Since morphine is ment of marked tolerance to their effects includ- selective for the mu receptor, it is thought that the ing their reinforcing effects (15,18). While the activation of this receptor is responsible for the precise mechanism of opiate tolerance is unclear, reinforcing characteristics of opiates (18,39,40,41). one hypothesis is that chronic exposure causes a The overall acute and chronic effects of opiate desensitivity of opioid receptors (15,58). Re- drugs in the brain involve many interactive brain peated activation of the receptors by the drug systems (39). Related to the function of en- causes an uncoupling of the receptor from the dogenous opioid neurotransmitters, opiate drugs internal cellular mechanisms that are activated produce a profound sense of euphoria and well- when the receptors are stimulated normally (58). being coupled with sedation, relaxation, and Experimental evidence also suggests that chronic increase in pain threshold in humans. exposure to opiate drugs may decrease the levels Acute administration-Opiates have an imm- of endogenous opioid neurotransmitters, contrib- ediate reinforcing effect and are readily self- uting to the development of tolerance (58). The administered by humans and animals in experi- decrease is believed to be due to an over mental situations (40). The weight of experimen- activation by the opiate drugs of mechanisms that tal evidence favors a role for dopamine in the normally regulate the levels of neurotransmitter rewarding effects of opiates, while other systems (58). may also be involved (18). Animal studies have Craving and withdrawal are two prominent shown that opiates increase the activity of dopam- characteristics of chronic opiate administration. ine neurons in the ventral tegmental area (18,39, In humans withdrawal is characterized by depres- 40,41). This increase is via an indirect mechanism sion, irritability, insomnia, nausea, and weakness (18). Within the ventral tegmental area neurons (18,36). Chronic morphine administration, like contain the inhibitory neurotransrnitter GABA. chronic cocaine administration, has been shown Those GABA containing neurons have mu recep- to produce changes in the expression of genes tors on them and form synapses with the dopam- involved in a number of intracellular mechanisms ine neurons. Since opioids also inhibit neural within neurons in the ventral tegmental area and activity, when the mu receptors are activated by nucleus accumbens (10). These changes may opiates, the GABA receptors release less GABA, contribute to the craving and feelings of dysphoria which decreases the inhibition on the dopamine associated with withdrawal. cells, causing the dopamine neurons to become The locus ceruleus, a nucleus in the brainstem, more active. The net effect of this disinhibition is has been implicated in the physical signs of opiate to increase activity in the ventral tegmental withdrawal (15,39,40). The locus ceruleus is neurons, which release doparnine in the nucleus composed mainly of neurons containing noradre- accumbens. This increase in dopamine activity naline. These neurons send fibers to numerous results in the rewarding and motor stimulating brain structures including the cortex, hippocam- properties of opiate drugs. In addition to the pus, and other structures in the front of the brain Chapter 3-The Neuropharmacology of Drugs of Abuse | 33

and receive fibers from various structures, includ- acute and long-term consequences of marijuana ing a strong excitatory input from other areas in use (2). the brainstem, The activity of locus ceruleus It has only been in the last few years that a neurons is inhibited by opioid neurotransrnitters specific receptor for THC has been identified in via activation of mu receptors (15). Animal the brain (16,30). This receptor is linked to a studies have shown that direct electrical stimulat- second messenger (14) and is localized to specific ion of these neurons produces symptoms similar brain regions including the hippocampus, cere- to those seen in opiate withdrawal (15). Locus bral cortex, cerebellum, and the axon terminals of ceruleus neurons become tolerant to the effects of fibers that arise in the basal ganglia (a brain opiates after chronic exposure (15,39). An in- structure in the front of the brain involved with creased stimulation of the neurons in the locus movement) and terminate in the globus pallidus (a ceruleus via their brainstem excitatory inputs is structure in the front of the brain involved in thought to occur during opiate withdrawal, result- movement and closely connected with the basal ing in the enhanced noradrenaline release at the ganglia) and substantial nigra (located in the many brain sites that receive inputs from the locus midbrain, next to the ventral tegmental area, it ceruleus (15). contains dopamine neurons that send fibers to the basal ganglia) (29,30). The characteristic cognitive (e.g., memory impairment) and motor (e.g., | Cannabis decreased motor coordination) effects of THC are The different types of drugs made from Canna- thought to be the result of its action on these bis sativa are distinguished by the plant parts used receptors (29). As with benzodiazepines, the in preparing the drug. Marijuana consists mainly identification of a specific receptor for THC of dried plant material such as cut leaves, stems, suggests that there may be a naturally occurring seeds, and the flowering tops of the plants. endogenous neurotransmitter in the brain that Hashish is the dried resin made from the flower normally interacts with the receptor. While not tops and sinsemilla is a variety of marijuana positively identified, several candidates have selected for its particularly potent effects and been proposed, including the chemical anan- harvested before seed formation. Cannabis is damide (16). most frequently smoked, resulting in the rapid Since smoking marijuana results in the inhala- delivery of the drug into the bloodstream, such tion of many potentially psychoactive com- that effects may be felt within minutes and last for pounds in addition to THC, the subjective effects 2 t0 3 hours. Cannabis may also be administered of marijuana vary somewhat among individuals orally. However, the plasma concentration is (2). The behavioral response to marijuana may lower and takes about an hour to peak. vary as a function of dose, setting, experience, and Cannabis sativa contains psychoactive can- expectation of the user, the cannabinoid content nabinoids. The primary psychoactive component of the sample, and the compounds that are of Cannabis sativa is the cannabinoid delta-9- produced as the marijuana is burned. Neverthe- tetrahydrocannabinol (THC). Most of the other less, several behavioral effects are generally cannabinoids are either inactive or weakly active. ascribed to marijuana use (32). The most promi- In addition, smoking marijuana produces hun- nent feature is an initial period of euphoria. The dreds of other compounds (2). While most euphoria is often followed by a period of drowsi- research has concentrated on evaluating the ness and sedation. Perception of time is altered molecular and biochemical mechanisms of THC and there is a dissociation of ideas, and distortions that underlie the actions of the cannabinoids, in hearing and vision. Some studies have docu- these other compounds can also play a role in the mented impairment on a variety of cognitive and 34 I Biological Components of Substance Abuse and Addiction

performance tasks involving memory, percep- develops to the mood, memory, motor, and tion, reaction time, learning, and motor coordina- performance effects of the drug (51). The mecha- tion (2). An amotivational syndrome, character- nism of this tolerance is thought to be a desensiti- ized by apathy, dullness and impairment of zation of the THC receptor, perhaps by some judgment, concentration and memory, along with alterations in its interaction with the second loss of interest in pursuit of conventional goals, messenger (2,51). has been described in the literature, and evidence Cessation of cannabinoid administration does shows that this syndrome is a result of chronic not give rise to an intense withdrawal syndrome intoxication (35). (2,51). Only a few animal studies show that any Acute administration-While marijuana pro- withdrawal symptoms result. Changes that have duces a feeling of euphoria in humans, in general, been observed include increased motor and groom- animals will not self-administer THC in con- ing activity in rats, altered susceptibility to trolled studies (29). Also, cannabinoids generally convulsion induced by electric shock in mice, and do not lower the threshold of the amount of increased aggressiveness in monkeys (51). In electrical stimulation needed to get animals to humans, withdrawal signs are relatively mild self-stimulate the brain reward system, as do other (2,51) and consist of changes in mood and sleep, drugs of abuse; although one series of studies has increased imitability and restlessness, anorexia, shown that in the inbred lewis rat, THC not only and mild nausea. As with all drugs the relative lowers the threshold for electrical self-stimulation intensity of the withdrawal syndrome is depend- but also enhances the release of dopamine in the ent on the quantity, frequency, and duration of nucleus accumbens (22). The enhancement of drug use. While a severe physical dependence dopamine release was blocked by drugs that block phenomenon is not associated with cannabis endogenous opioid activity (22) indicating that withdrawal, the probability of developing a form endogenous opioids can regulate this response. of craving is high (2). The mechanism for these The fact that these results have been observed in various withdrawal effects is unknown, but it is an inbred strain of rat indicates that they have likely related to the unmasking of the desensitized some inherited variation related to the mechanism receptors on drug cessation. Also, both the of THC. Since THC receptors are not directly tolerance and withdrawal phenomena may be associated with dopamine neurons (29) and the related to alterations in the as yet unidentified dopamine response that has been observed is endogenous neurotransmitter that interacts with modulated by opioids, it is likely that the effects the THC receptor (5 1). of cannabinoids on dopamine circuits involved in reward are indirect and different from those of drugs, such as cocaine and morphine that directly | Lysergic Acid Diethylamide affect dopamine levels and produce craving and Lysergic acid diethyklamide (LSD) is one of a drug-seeking behavior (29). Nonetheless, the broadly defined class of drugs known as psyche- observation that the ability of animals to recog- delics. Other psychedelics include mescaline and nize the intoxicating effects of THC can be psilocybin. The effects of the psychedelics are mimicked by drugs that selectively activate the similar, but LSD is the most potent (13). These THC receptor indicates that these effects are drugs distort the perception of space and time, and mediated through the THC receptor (9,23). produce exaggerated sensory phenomena in vi- Chronic administration—Tolerance readily sion, hearing, and touch. The subjective effects develops to the behavioral and pharmacological associated with psychedelic use are strongly effects of THC in both humans and animal determined by a number of factors such as setting, experimental models (2,5 1). In humans, tolerance expectations, user’s personality, and dose. In Chapter 3-The Neuropharmacology of Drugs of Abuse | 35

some cases, adverse psychiatric effects occur non of flashbacks, in which the perceptual changes including ‘bad trips’, panic reactions, and even associated with LSD spontaneously appear after psychotic episode during intoxication. While drug cessation, are reported to occur in about 23 these drugs are some of the most powerful percent of regular users (31). It unclear whether psychoactive drugs known and can have adverse flashbacks represent a withdrawal syndrome and consequences, their dependence potential, as are related to, or predictive of, hallucinogen measured by their reinforcing properties and dependence (13). neuroadaptive response, is low as compared with the other drugs discussed in this report. Psyche- delic use has undergone cycles of popularity, such SUMMARY as during the 1960s, and serves as an example of Studies of the pharmacological actions of drugs how extrinsic societal factors can affect drug use, of abuse indicate that their reinforcing properties in addition to the intrinsic pharmacological ac- may be due to actions on a common neural circuit. tions of a drug. While the mechanisms involved for all drugs of Acute administration—LSD’s psychedelic abuse have not been completely described, many, properties are a result of its actions on the either directly or indirectly, activate MCLP. Such serotonin neurotransmitter system (1 1,26). LSD drugs include cocaine, amphetamines, opiates, is thought to stimulate the various receptor sedatives, and nicotine. For other drugs of abuse subtypes for serotonin, and has particular potency the precise relationship, if any, to the brain reward in activating the serotonin autoreceptor (3). A system is unclear. similar activation of the serotonin system is seen Repeated administration of all drugs of abuse with MDMA, which is a derivative of ampheta- is associated with neuroadaptive responses. In mine and has both dopamine and serotonin general, tolerance develops to at least some of stimulating properties. Unlike LSD, MDMA their effects although the specific details of the stimulates serotonin neurotransmission by block- biological mechanisms underlying these changes ing its reuptake into the presynaptic terminal (l). are not completely understood. In terms of This action on serotonin gives MDMA psyche- promoting substance abuse, an important action is delic properties in addition to its amphetamine- the development of tolerance to the reinforcing like stimulating properties. To date, no evidence properties of a drug. Available evidence suggests confirms that LSD supports self-administration in animal studies (13). that tolerance develops to the reinforcing proper- Chronic administration—Tolerance devel- ties of cocaine, alcohol, PCP, and opiates. A ops rapidly to LSD and other psychedelics when withdrawal syndrome is associated with most they are repeatedly administered and the extent of drugs of abuse, though the severity varies. Barbi- the tolerance is greater than what is observed with turates, alcohol, stimulants, opiates, and benzodi- other drugs such as PCP or alcohol (13). The azepines produce pronounced and sometimes mechanism of LSD tolerance is unclear. Since severe withdrawal symptoms, while those for LSD stimulates serotonin receptors and a typical nicotine and caffeine is less intense. A mild response of receptors to continued activation is a withdrawal is associated with cannabis use; while desensitization process, it is possible that sero- there is no evidence of a withdrawal syndrome tonin receptor desensitization plays a role. related to LSD. Certain aspects of withdrawal, Currently, there is no evidence that a with- such as changes in mood and motivation, induced drawal syndrome is associated with termination by the chronic drug state may be key factors to of chronic hallucinogen use (13). The phenome- relapse and drug-seeking behavior. 36 I Biological Components of Substance Abuse and Addiction

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Chapter 3-The Neuropharmacology of Drugs of Abuse 137

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46. Morgan, W.W., “Abuse Liability of Barbiturates 54. Saunders, P.A., and Ho, I.K., “Barbiturates and and Other Sedative-Hypnotics, Advances in the GABA~ Receptor Complex,” Progress in Alcohol and Substance Abuse 9:67-82, 1990. Drug Research 34:261-286, 1990. 47. Morrow, A.L., Montpied, P., and Paul, S. M., 55. SimsOn, P.E., Criswell, H.E., Breese, G.R., “Inhi-

“Ethanol and the GABAA Receptor Gated Chlo- bition of NMDA-Evoked Electrophysiologica.1 ride Ion Channel,” R.E. Meyer, G.F. Koob, M.J. Activity by Ethanol in Selected Brain Regions: Lewis, et al. (eds.), Neuropharmacology of Etha- Evidence for Ethanol-Sensitive and Ethanol- nol: New Approaches (Boston, MA: Birkhauser, Insensitive NMDA-Evoked Response,” Brain 1991). Research 607:9-16, 1993. 48. Murphy, J.M., McBride, W.J., Luming, L., et al., 56. Stolerrnan, I.P., and Shoaib, M., “TheNeurobiol- “Regional Brain Levels of Monoamine in Alcohol- ogy of T*acco Addiction,” Trench in Pharmac- Preferring and Non-Preferring Lines of Rats,” ological Sciences 12467473, 1991. Pharmacology, Biochemistry, and Behavior 16: 57. Temant, F. S., Rawson, R.A., and McCann, M., 145-149, 1982. “Withdrawal From Chronic Phencycl.idine De- 49. Nehlig, A., Daval, J.L., and Deb~, G., “Caffeine pendence With Desipramine,” American Journal and the Central Nemous System: Mechanisms of of Psychiatry 138:845-847, 1981. Action, Biochemical, Metabolic and Psychostim- 58. Trujillo, K.A., and Akil, H., “Opiate Tolerance ulant Effects,” Brain Research Reviews 17:139- and Dependence: Recent Findings and Synthe- 170, 1992. sis,” The New Biologist 10:915-923, 1991. 50. O’Malley, S.S., Jaffe, A.J., Chang, G., et al., 59. Volpicelli, J.R., Alter’man, A. I., Hayashadi, M., et “Naltrexone and Coping Skills Therapy for Alco- al., “Nakrexone in the Treatment of Alcohol hol Dependence: A Control.kxi Study,” Archives Dependence,’ Archives of General Psychiatry of General Psychiatry 49:881-887, 1992. 49:876-880, 1992. 51. Pertwee, R. G., ‘‘Tolerance to and Dependence on 60. Weiss, F., Hurd, Y.L., Ungerstedt, U., et al., Psychotropic Cannabinoids,” J. Pmtt (cd.), The “Neurochernical Correlates of Cocaine and Etha- Biological Basis of Drug Tolerance and Depend- nol Self-Administration,’ P.W. Kalivas, and H.H. ence (London: Academic Press, 1991). Samson (eds.), The Neurobiology of Drug and 52. %rnson, H.H., and HMIiS, R. A., “Neurobiology Alcohol AdUiction, Annals of the American Acad- of Alcohol Abuse,” Trends in Pharmacological emy of Sciences 654:220-241, 1992. Science 13:206-211, 1992. 61. White, F. J., and Wolf, M. E., “PsychomotorStirn- 53. Samson, H. H., Tolliver, G. A., Haraguchi, M., et ulants, ” J. Pratt (cd.), The Biological Basis of al., “Alcohol Self-Administration: Role of Mes- Drug Tolerance and Dependence (hmdon: Aca- olirnbic Dopamine, ” P.W. Kalivas, and H.H. demic Press, 1991). Samson (eds.), The Neurobiology of Drug and 62. Woolverton, W.L., and Johnson, K.M., “Neurobi- Alcohol Addiction, Annals of the American Acad- ology of Cocaine Abuse,’ Trend in PharrnacoZ- emy of Sciences 654:242-253, 1992. ogical Sciences 13:193-200, 1992. _-—

Genetics 4

hy does one person become dependent on drugs while another, exposed to the same environment and experiences, does not? As progress in understanding the role of genetics in various conditions and diseases increases,w there has been a realization that there is likely to be a genetic component to substance abuse and addiction. That is, inherited differences among individuals affect their response to drugs. To date, much of the work done in this field is related to alcoholism, less is known about the genetics of other drugs of abuse. Studies in both humans and animals contribute to the understanding of genetic factors in substance abuse and dependence. Human studies shed light on the question of whether drug dependency is transmitted between generations. In addition, the study of individuals with substance abuse problems as well as animal studies provide information about what is actually inherited. For example, are there genetic differences in sensitivity and responsiveness to drugs? And, if yes, are the differences drug-specific, or are they related to general mechanisms associated with the actions of all abused drugs? Finally, the tools of modern molecular biology can be used to identify the specific genes that control various cellular and biochemical functions possibly involved in an inherited component of substance abuse and addiction. While the existence of inherited differences seems likely, a genetic component alone probably is insufficient to precipitate substance abuse and addiction. Unlike disorders such as Hunt- ington’s disease and cystic fibrosis, which result from the presence of alterations in a single gene, substance abuse is likely

39 40 | Biological Components of Substance Abuse and Addiction

to involve multiple genes that control various I Family Studies aspects of the biological response to drugs. In addition, the complex nature of drug dependency, ALCOHOLISM involving many behavioral and environmental References to a familial tendency or hereditary factors, indicates that any genetic component acts ‘‘taint’ of alcoholism date back to classical times in consort with other nongenetic risk factors to (44); an observation repeatedly confirmed by contribute to the development of substance abuse family studies. While not all cases axe familial, and addiction. Thus, neither the presence nor the risk of alcoholism consistently has been found absence of a genetic factor ensures development to be higher among frost-degree relatives (i.e., parents, siblings, children) of alcoholics as com- of, or protection from, drug addiction. pared to the general population (79). Moreover, while family studies can establish that a disorder DO INHERITED FACTORS EXIST? (or liability to a disorder) is transmitted; in A number of confounding factors complicates general, they are unable to distinguish between the study of genetic transmission of substance biological and cultural transmission (though this abuse liability in humans. One is the high issue can be evaluated in large family studies by incidence of psychiatric conditions among sub- analyzing multiple classes of relatives with differ- stance abusers (104), which raises questions ing degrees of genetic relatedness). Results of numerous family studies indicate about the role of psychiatric comorbidity in that alcoholism segregates within families, with liability to illicit drug addiction. In particular, male first-degree relatives of alcoholics having a antisocial personality disorder (ASPD) is often higher incidence (ranging from 27 to 54 percent) associated with substance abuse. One study than female first-degree relatives (6 to 17 percent) shows that 84 percent of individuals with ASPD as compared to first-degree relatives of nonalco- also have some form of substance abuse during holics (20 percent of males, 4 percent of females) their lifetimes (104). Other psychiatric conditions (49,103,133). In fitting models of inheritance to that may be associated with substance abuse are family data, researchers concluded that observed depression, anxiety disorders, manic-depression, patterns of inheritance were consistent with the and schizophrenia. hypothesis that familial factors predisposing to Another issue related to studies of the genetics alcoholism were the same in men and women, but of liability to abuse of specific drugs is that many that nonfamilial environmental factors exerted drug abusers engage in multiple drug use, so exam- more influence in the development of alcoholism ining any familial trends in the use of a particular in women (20). Familial alcoholics (those with at drug becomes difficult. Finally, rates of illicit least one relative with alcoholism) appear to have drug use show strong secular trends. Even assum- earlier onset, more antisocial symptoms, more ing a vulnerability to drug-specific addictions, social complications of alcohol use, and worse there might be tremendous variations in expres- treatment outcome than nonfamilial alcoholics sion of addiction, simply because of differences (38,93,111). in drug availability over time: No matter how vul- Familial is not identical to genetic, and in the nerable an individual might be, addiction requires case of alcoholism, the familial patterns of exposure. Such issues often hamper studies on the inheritance are not consistent with those of a genetic transmission of drug liability. purely genetic condition (58,109). In addition, evidence suggests that the transmissibility of alcoholism has increased over time (102). Thus, any genetic factors promoting the development of Chapter 4-Genetics | 41

alcoholism are significantly moderated by non- Little research has been done to test hypotheses genetic influences. regarding familial transmission of liability to addiction to specific substances other than opiates OTHER DRUGS or alcohol. One study involving 350 treated drug Fewer family studies have been conducted on abusers and 1,478 relatives, found that alcoholism the genetic transmission of liability to other drugs was equally common among relatives of individ- of abuse. Nonetheless, the evidence available uals who preferentially abused opiates, cocaine, suggests that, as in the case of alcohol, addiction or sedative-hypnotics (27 percent, 31 percent, and to other psychoactive substances appears to run in 24 percent of male relatives, respectively), whereas families. relatives of sedative-hypnotic users were subject One study found evidence for familial aggrega- to diagnoses of other substance abuses (2 percent tion of drug use, based on family history obtained of male relatives, versus 11 percent of male from individuals admitted for substance abuse relatives of opiate abusers and 16 percent of male treatment (78). However, this study also com- relatives of cocaine abusers) (80). bined use of all illicit drugs into one category and relied on self-reports by the subject on his or her drug use as well as that of family members. In a I Twin and Adoption Studies large family interview study comparing 201 While family studies can establish that a opiate addicts and 82 normal controls, as well as disorder (or liability to a disorder) runs in a interviews of 1,398 first-degree relatives of these family, they generally are unable to distinguish ‘subjects, the relatives of opiate users had elevated between biological and cultural transmission. rates of drug addiction as compared with the However, two other methods are used to help controls (105). In addition there was an associa- disentangle the effects of genetic and nongenetic tion between opiate use and the presence of factors. Adoption studies compare the presence of ASPD. Further analysis of these data revealed a trait among biological versus adoptive family that the incidence of both drug abuse and ASPD members or other control groups. In this way was higher among the siblings of the opiate individuals that share the same environment but subjects than among their parents (69,70). different genetic heritages, or vice versa, can be Some studies note a familial association be- compared. Twin studies, by contrast, involve tween opiate addiction and alcoholism (65). siblings raised in the same environment, but However, another family history study (51), compare how often identical twins, who are 1 comparing families of 32 alcoholics, 72 opiate genetically identical, and fraternal twins, who addicts, and 42 individuals addicted to both are not, are similar, or concordant, for a trait. A substances, found that while both opiate addiction high concordance rate for a trait among identical and alcoholism clustered within families, co- twins versus fraternal twins usually indicates a occurrence of the disorders within families oc- genetic component for the trait. curred no more frequently than expected by chance, thus supporting the hypothesis of inde- TWIN STUDIES pendent transmission. However, a later study of Evidence fromn twin studies suggests genetic 201 opioid addicts and 877 of their first-degree influences on drinking‘ patterns as well as alcohol- relatives also showed familial aggregation of both related problems. Results from twin studies alcoholism and depressive illness suggesting a demonstrate genetic influences on measures of possible co-occurence of the disorders (64). alcohol consumption such as abstention, average

1 Fraternal twins share the same in utero environment but are genetically no more similar than any two siblings, 42 | Biological Components of Substance Abuse and Addiction

alcohol intake, and heavy alcohol use (50,60,92). ADOPTION STUDIES Twin studies also indicate an inherited risk for Adoption studies have supported the role of smoking (24). heritable factors in risk for alcoholism (1 1,18,1 17). When evaluating how alcoholism develops, The results from a series of studies conducted in twin studies generally support the existence of Denmark during the 1970s are typical. Of 5,483 genetic influences on the development of the nonfamily adoption cases from the copenhagen disorder. One study found a higher concordance area between 1924 and 1947, the researchers rate for alcohol abuse between identical twins (54 studied 55 male adoptees, and later compared 20 percent) versus fraternal twins (28 percent) (57), adoptees with 30 nonadopted brothers. They also while two subsequent studies found no such studied 49 female adoptees, comparing them with relationship (48,92,). A 1991 study (94) examined 81 nonadopted daughters of alcoholics. Compari- 50 male and 31 female identical twin pairs and 64 sons also were made with matched control male and 24 female fraternal twin pairs, with 1 adoptees. The Copenhagen study revealed that member of the pair meeting alcohol abuse or adopted-away sons of alcoholic parents were four dependence criteria. The study found that identi- times as likely as adopted-away sons of nonalco- cal male twins differed fromn fraternal male twins holics to have developed alcoholism; evidence in the frequencies of both alcohol abuse and also suggested that the alcoholism in these cases dependence as well as other substance abuse was more severe. The groups differed little on and/or dependence. On the other hand, female other variables, including prevalence of other identical and fraternal twins were equally likely to psychiatric illness or “heavy drinking.” Being abuse alcohol and/or become dependent on other raised by an alcoholic biological parent did not substances, but identical female twins were more further increase the likelihood of developing likely to become alcohol dependent. Another alcoholism. That is, rates of alcoholism did not study of 356 twin pairs also found higher identical differ between the adopted-away children and than fraternal rates of concordance for problems their nonadopted brothers. In contrast, daughters related to alcohol and drug use as well as conduct of alcoholics were not at elevated risk of alcohol- disorder (77). The same study also noted that ism. Among adoptees, 2 percent had alcoholism among men, heritability was greater for early rather than late onset of alcohol problems, whereas (and another 2 percent serious drinking prob- no such effect was seen for women. Finally, a lems), compared with 4 percent of alcoholism study of 1,030 female twin pairs found evidence among the adopted controls and 3 percent among for substantial heritability of liability to alcohol- nonadopted daughters (44). ism, ranging from 50 to 60 percent (61). Another analysis examined factors promoting Thus, twin studies provide general agreement drug abuse as well as alcoholism (17). In this that genetic factors influences certain aspects of study, all classes of illicit drug use were collapsed . . drinking. Most twin studies also show genetic into a single category of ‘‘drug abuse. ” Most of influence over pathological drinking,“ including the 40 adopted drug abusers examined had the diagnosis of alcoholism, which appears (like coexisting ASPD and alcoholism; the presence of many psychiatric disorders) to be moderately ASPD correlated highly with drug abuse. Among heritable. Whether genetic factors operate compa- those without ASPD, a biological background of rably in men and women, and whether severity of alcoholism (i.e., alcoholism in a biological par- alcoholism influences twin concordance is less ent) was associated with drug abuse. Also, clear. How psychiatric comorbidity may affect turmoil in the adoptive family (divorce or psychi- heritability of alcoholism also remains to be atric disturbance) was also associated with in- studied. creased odds for drug abuse in the adoptee. Chapter 4-Genetics |43

Finally, results from other adoption studies available about alcoholism as compared with suggest two possible forms of alcohol abuse other drugs of abuse. (12,19). The two forms have been classified as First, specific inherited risk markers for alco- “milieu-limited” or type 1 alcohol abuse and holism and other substance abuse can be identi- “male-limited” or type 2 alcohol abuse (21). fied. A risk marker is a biological trait or Type 1 alcohol abuse characterized by mild characteristic that is associated with a given alcohol problems and minimal criminal behavior condition. Thus, if an individual is found to have in the parents, is generally mild, but occasionally an identified marker for substance abuse, he or severe, depending on presence of a provocative she is at risk for developing a drug dependency. environment. Type 2 is associated with severe To date, no biological characteristic has been alcohol abuse and criminality in the biological clearly identified as being a risk marker for either fathers. In the adoptees, it was associated with alcoholism or substance abuse, although evidence suggests some possible candidates. The identif- recurrent problems and appeared to be unaffected by postnatal environment. cation of a valid and reliable risk marker could provide important information about the funda- Insummary, adoption studies of alcoholism mental mechanisms underlying substance abuse clearly indicate the role of biological, presumably and addiction and would be an invaluable aid in genetic, factors in the genesis of alcoholism. They diagnosis and treatment. do not exclude, however, a possible role for Second, inherited differences in biochemical, nongenetic, environmental factors as well. More- physiological, and anatomical processes related over, evidence suggests more than one kind of to differences in drug responses might be identi- biological background conducive to alcoholism. fied and studied. Thorough biological assays can In particular, one pattern of inheritance suggests be performed using animal models of substance a relationship between parental antisocial behav- abuse. Animal models of substance abuse consist ior and alcoholism in the next generation. Thus, of strains of animals (usually rodents) that have adoption studies, like other designs, suggest that been selectively bred to either exhibit a prefer- even at the genetic level, alcoholism is not a ence for taking a drug, exhibit a preference for not homogeneous construct. taking a drug, or differ in some way in their behavioral or physiological response to a drug. WHAT IS INHERITED? Thus, such differences represent inherited traits related to drug-taking behavior, and these animals Although studies indicate that genetics contrib- can be studied to determine what biological utes to alcoholism and probably other drug abuse, mechanisms are involved in the expression of they lack information about what exactly is such traits. inherited. For example, do individuals with a Finally, the genetic technique of linkage analy- family history of drug abuse have an increased sis can narrow the area on a chromosome where susceptibility or sensitivity to the effects of drugs a gene may be located. It can lead to the with reinforcing properties? If a susceptibility identification of the gene itself, which, in turn, exists, what are the biological mechanisms that can improve the understanding of the molecular underlie it? To understand what might be inher- events that underlie the expression of the gene. ited, both individuals who have a substance abuse There have been few genetic linkage studies problem and animals models of substance abuse related to substance abuse since few specific are studied. Various types of information can be biological traits associated with drug dependency derived from these studies. As with family, twin, have been identified. Some studies in humans and adoption studies, much more information is have been carried out related to alcoholism but the 44 I Biological Components of Substance Abuse and Addiction

findings of these studies are contradictory and Currently, both EEG and ERP findings seem inconclusive (see later discussion). best viewed as possible markers. Further studies are needed to confirm or refute the positive results that have been observed. In addition, while ERP Specific Risk Markers findings in particular might relate to aspects of sensory, perceptual, or cognitive functioning that ELECTROPHYSIOLOGICAL ACTIVITY may differ among those at risk for alcoholism, Attempts to correlate distinctive patterns of how such differences contribute to risk for spontaneous electrical activity of the brain with alcoholism and perhaps substance abuse is not alcoholism and substance abuse have been equiv- well understood. ocal. A few studies have found distinctive electro- encephalograph (EEG) patterns in individuals at BIOCHEMICAL ASSAYS risk for alcoholism (32,39), but others have not Serotonin—Results over the last two decades (31,59,101). Similarly, the use of alcohol chal- from both human and animal studies have sup- lenge (i.e., giving the subject alcohol and then ported a relationship between low levels of recording EEG) on subjects at high risk for central nervous system (CNS) (i.e., brain and alcoholism has likewise yielded inconclusive spinal cord) serotonin and impulsive and violent results. The rationale for challenge studies rests behavior (130,131). Since problematic use of on the observation that alcohol has been shown to alcohol (as well as other drugs) has long been affect resting EEG, and thus might have a associated with a wide range of violent behavior, differential effect on those at low and high risk for scientists have examined the relationship be- alcoholism (100). Again, some studies have seen tween alcoholism and serotonergic abnormalities. distinctive responses (100,101), while other have While a consistent relationship between alcohol- not (39,59). ism and low CNS levels of serotonin and its A logical extension of studying resting EEG metabolizes is lacking, mounting evidence sup- activity is examining event-related potentials ports the presence of such abnormalities in a (ERPs). ERPs are patterns of brain electrical subgroup of alcoholics with early-onset problems activity produced in response to a particular and a history of violence (16,67,68,107,130). stimulus (e.g., auditory, visual); they can reflect Because measures of serotonin activity are a variety of sensory and cognitive processes. difficult to obtain, researchers have used pharma- Since ERPs may reflect heritable differences in cologic probes of serotonin function, such as cognitive function or capability that may in turn hormonal response to drugs that affect serotonin. contribute to liability to alcoholism, some have These indirect measures have also indicated a suggested that ERP changes may allow discrimin- relationship between impulsivity, substance abuse, ation between those at low and high genetic risk and abnormal serotonin function (37,42,71,83). for alcoholism. The results of these studies have For alcoholism, given that early-onset alcohol- also been equivocal. Some have found character- ism and ASPD overlap substantially (16), the istic responses among individuals at risk for specificity of the serotonin findings is unclear, alcoholism (3,4,33,52,53,89,90,125) while others especially as similar results have been found in have not (95,96,97,98). In addition to being substance abusers with ASPD (71). However, at equivocal, the specificity for alcoholism of such least one report has indicated that, even after findings is unclear. In particular, it is not yet controlling for the presence or absence of ASPD known whether similar findings might be identi- and illicit drug abuse, other neurochernical fin- fied in subjects with (or at risk for) illicit drug dings remained significantly associated with alco- abuse. holism (106). While further work might delineate Chapter 4-Genetics| 45

the relationship between decreased CNS sero- presence of these gene variations in an individual tonin levels and Specific psychiatric syndromes, accounts for variations in the metabolism of current evidence suggests relatively specific bio- alcohol (54). Thus, the presence of these genes logical differences may exist between early- and can also effect alcohol consumption. For exam- late-onset alcoholics; raising the possibility of ple, the gene variations that code for the ineffec- defining biologically homogeneous subgroups. tive form of aldehyde dehydrogenase is not only Aldehyde and alcohol dehydrogenase en- less common in alcoholics, but also is rare in zymes-Many Asians rapidly develop a promi- Japanese patients with alcoholic liver disease nent facial flush following ingestion of a small (27, 121,135). Despite identification of such genes, amount of alcohol. Continued drinking leads to the relationship between their inheritance and the nausea, dizziness, palpitations, and faintness. familial transmission of alcoholism remains un- This reaction is due to inactivity in individuals’ studied. aldehyde dehydrogenase, an enzyme that helps Alcohol challenge-A number of studies have metabolize (i.e., break down) alcohol in the body. been conducted investigating the effect of admin- Ineffective enzyme activity results in a buildup of istering alcohol to young adult sons of alcoholics the chemical acetaldehyde in the blood following (99). These studies indicate that, despite similar- alcohol consumption. Clinicians have taken ad- ity of blood alcohol levels, sons of alcoholics vantage of the aversive properties of acetaldehyde demonstrate less intense subjective responses to buildup by using the drug Antabuse to inhibit alcohol, as well as less intense upper body sway aldehyde dehydrogenase, thus inducing a severe (110,111,113,114). Thus, one mechanism by form of the adverse reaction in abstinent alcohol- which alcoholism might develop is that since ics who begin to drink (30,135). these individuals have less of a reaction to Alcohol dehydrogenase is another enzyme alcohol, they would find it more difilcult to involved in the metabolism of alcohol. A mutant self-regulate alcohol consumption, thus increas- form of alcohol dehydrogenase also produces a ing the risk of developing dependence. In con- transient increase in the acetaldehyde concentra- junction with these findings, other studies have tion after alcohol ingestion. This form of the found that sons of alcoholics demonstrate slightly enzyme also has been reported in Asian popula- lower levels of certain hormones (i.e., prolactin, tions. cortisol, adrenocorticotropin hormone (ACTH)) The two enzymes, aldehyde and alcohol dehy - after ingesting alcohol as compared to controls drogenase, probably interact in some individuals (82,1 14,115,116,1 18). The relationship, if any, of to amplify the adverse reaction to alcohol con- these decreased hormonal levels to alcohol consumption (129). Since this reaction discourages sumption is unclear. heavy drinking,“ the observation that it commonly occurs in some populations where alcoholism is COGNITIVE DIFFERENCES relatively rare suggests that alcohol and aldehyde Study of high-risk populations (e.g., sons of dehydrogenase mutations might be a major deter- alcoholics) has revealed temperamental, as well minant of alcohol consumption, abuse, and de- as biological, differences between high-risk and pendence. This would seem to hold true for control subjects, leading to the suggestion that Taiwan and Japan where the reaction occurs in 30 vulnerability to alcoholism can be conceptualized to 50 percent of individuals. from a behavior-genetic perspective (127). Heri- The genetics of the aldehyde and alcohol table, constitutional differences, in other words, dehydrogenases are well described. The produc- might affect temperament and, hence, risk for tion of the different forms of these enzymes is alcoholism and addiction to other drugs. In caused by variations of their normal genes. The particular, these differences might influence cog- 46 | Biological Components of Substance Abuse and Addiction

nitive styles, learning ability, and capability to characteristics supports a genetic link to these control one’s own behavior. traits. In general, it appears that sons of alcoholics Dopamine and alcohol intake-Studies of demonstrate group differences from low-risk dopamine content in the brains of two different populations in that the former tend to have strains of rats bred for either preference or impairment on tests of cognitive development, nonpreference for alcohol have found 25 to 30 academic achievement, and neuropsychological percent lower levels of dopamine in the nucleus function (34,12,8). However, the magnitude of accumbens and the olfactory tubercle of the these differences may depend greatly on how the alcohol-preferring rats (45,74,86). No other dif- population is ascertained. To date, little is known ferences in dopamine content have been observed of what specific psychological, temperamental, or in other brain areas. These data suggest an cognitive factors might distinguish between high- abnormality in the dopamine system projecting risk subjects who actually go on to develop from the ventral tegmental area to limbic regions alcoholism from those who do not (128). (nucleus accumbens and/or olfactory tubercle) of the alcohol-preferring rats. Since this system is I Biological Mechanisms thought to be involved in mediating the actions of . various drugs of abuse (see ch. 2) and alcohol is Animals that have been bred for specific thought to increase dopamine levels in the system characteristics are a valuable tool in drug use and (see ch. 3), it may indicate that an abnormal abuse research. For example, certain strains of functioning of the mesocorticolimbic dopamine rodents differ in their response to the analgesic system might be involved in promoting high and body temperature regulating effects of mor- alcoholdrinking “ behavior. That is, the alcohol phine, the motor activating effects of stimulant preference may be related to the ability of alcohol drugs, and the convulsant producing properties of to compensate for the abnormality. The nature of benzodiazepines (28,122). Since the essential this abnormality is unknown but may be due to characteristic of human drug abuse and addiction one or more of the following factors: decreased is persistent drug-seeking behavior, the most dopamine synthesis, a lower number of dopamine salient models are those of genetic differences in neurofibers, and/or reduced functional activity of drug self-administration and the factors associ- dopamine neurons. ated with it (e.g., tolerance). While there are some Some evidence exists that the mesocortico- genetic models of self-administration or prefer- limbic dopamine system may respond to systemic ence for different drugs (i.e., alcohol, opiates, ethanol administration to a greater degree in the cocaine) (28,41), more information is available alcohol-preferring strains than in the nonprefer- about the hereditary biological mechanisms that ring strains. Studies have found that levels of underlie the self-administration of alcohol than dopamine metabolizes were higher in areas of this other drugs. system (i.e., caudate nucleus, medial prefrontal cortex, and olfactory tubercle) after ingestion of ALCOHOL alcohol in alcohol-preferring rats as compared to A general working hypothesis is that alcoholics nonpreferring rats (35,36). Also, one study has are sensitive to the low-dose rewarding properties reported that the oral self-administration of alco- of alcohol, are less sensitive to the high-dose hol, under experimental conditions where the actions of ethanol (i.e., have a higher aversive animal was allowed to receive alcohol as a reward threshold) and develop tolerance to the aversive for performing a task, increased the synaptic effects of alcohol. The fact that rats can be levels of dopamine significantly more in the selectively bred to have such alcohol drinking nucleus accumbens of these alcohol-preferring ...... -- —.

Chapter 4-Genetics | 47

rats than in nonpreferring rats (132). It was also of the areas found to have low serotonin levels established that the alcohol-preferring strain of (i.e., hypothalamus, hippocampus) may be in- rats will self-administer alcohol directly into the volved in mediating the aversive effects of ventral tegmental area (73,74). These studies alcohol. Since the development of tolerance to the suggest that the mesocorticolimbic dopamine aversive actions of alcohol is one possible charac- system is involved in regulating alcohol drinking teristic of alcoholic abuse, a deficiency in sero- behavior and that alcohol may be a stronger tonin in these areas may be an innate factor positive reinforcer in alcohol-preferring rats than promoting tolerance to the aversive effects of in the nonpreferring rats. ethanol in alcohol-preferring lines of rodents. Differences in dop amine receptor populations Further study of one of the rat strains used in have also been reported. Two genetically deter- these studies showed that low serotonin in the mined high-alcohol seeking lines of rats have alcohol-preferring line compared with the non- been reported to have fewer of one type of preferring line was due to fewer serotonin con- dopamine receptor (i.e., the D2 receptor) in their taining axons (137). This study found fewer limbic system compared with the nonalcoholic serotonin presynaptic fibers forming synapses in rats (74,124), Twenty percent fewer D2 receptors the nucleus accumbens, frontal cortex, cingulate were observed in the olfactory tubercle and cortex, and hippocampus of alcohol-preferring nucleus accumbens of these rats. These studies, rats. These results suggest that the low serotonin along with genetic linkage studies (see later is the result of structural differences in the CNS discussion), provide support for the involvement serotonin system rather than lower production of of the D2 receptor in alcohol-preference. serotonin. Examination of this same strain of rats Serotonin and alcohol intake--Examination found that there were increased numbers of one of alcohol-preferring and nonpreferring rats has type of post-synaptic serotonin receptor in areas indicated a relationship between high alcohol of the frontal cortex and hippocampus (73,76,134). preference and a deficiency in the CNS serotonin This increase in the number of serotonin postsyn- system. A number of studies have reported 10 to aptic receptors may represent a compensation for 30 percent lower levels of serotonin and its the lower number of presynaptic serotonin fibers. metabolizes in the brains of alcohol-preferring No such increase in receptors was found in the rats as compared with alcohol nonprefening rats strain of rats with normal levels of brain serotonin (45,66,74,84,85,86). Only one study, using a activity discussed earlier (62). strain of rats not used in any of the others, did not Overall, the animal data favors an inverse find lower brain serotonin levels (63). Areas of relationship between the functioning of the CNS the brain found to have low serotonin levels serotonin system and alcohol drinking behavior. include the cerebral cortex, frontal cortex, nu- Thus, innate low functioning of the serotonin cleus accumbens, anterior and corpus striatum, system may be associated with high alcohol septal nuclei, hippocampus, olfactory tubercle, preference. In support of this concept, some thalamus, and hypothalamus. studies have found lower cerebrospinal fluid Since several of these CNS regions may be serotonin metabolize concentrations in alcoholics involved in mediating the rewarding properties of than in various control populations (2,14). drugs of abuse, including alcohol, these findings GABA and the actions of alcohol—Evidence suggest a relationship between lower contents of indicates that alcohol can exert some of its serotonin in the brain and high alcohol preference. antianxiety and intoxicating effects by potenti- Evidence suggests that the serotonin system is ating the actions of the neurotransmitter gamma involved in regulating the activity of the dopa- amino butyric acid (GABA) at the GABAA mine mesocorticolimbic system ( 136). Also, some receptor (see ch. 3) and that this receptor might be 48 I Biological Components of Substance Abuse and Addiction

involved in mediating alcohol drinking behavior Alcohol withdrawal severity—Animal mod- of alcohol-preferring rats (75). However, little has els have been developed for differential genetic been published that indicates an innate abnormal- susceptibility to alcohol withdrawal. For exam- ity may exist in the GABA system that could be ple, withdrawal seizure-prone mice display a associated with alcohol preference. A recent higher incidence of convulsions than do seizure- study examined the densities of GABA contain- resistant mice when exposed to identical alcohol ing fibers in the nucleus accumbens and other concentrations (29). Other studies suggest that brain areas of two different strains of alcohol- this alcohol withdrawal reaction is mediated by preferring and nonprefering rats (55). The results an increased sensitivity of channels for calcium of this study indicated a higher density of GABA ions, coupled to receptors for excitatory amino fibers in the nucleus accumbens of the alcohol- acids (46,47). Several results have emerged in preferring rats compared with the nonpreferring studies of these mouse lines that are potentially rats. There were no differences between the important for understanding drug abuse. For respective lines in the other regions. These results example, studies indicate that independent ge- suggest alcohol preference may involve an innate, netic factors control alcohol sensitivity, toler- abnormal GABA system within the nucleus ance, and dependence, suggesting that these accumbens. features of drug abuse are maintained by different The experimental drug RO 15-4513 binds to neurobiological mechanisms (28). In addition, the the GABAA-BDZ-Chloride channel receptor com- alcohol withdrawal seizure-prone mice have more plex (see ch. 3) and is known to block the actions severe withdrawal to other depressant drugs (i.e., of alcohol at this receptor (126). The administra- diazepam, phenobarbital, nitrous oxide) (6,7,8) tion of RO 15-4513 reduced alcohol but not water suggesting that a group of genes acts to influence intake in a study using one of the alcohol- drug withdrawal severity not only to alcohol, but preferring line of rats (75). The blocking effect of also to a number of other depressant drugs. RO 15-4513 on alcohol intake could itself be blocked by administration of a drug that blocks OTHER DRUGS the benzodiazepine receptor. These results indi- A variety of strains of rats and mice has been cate that the GABAA-BDZ-chloride channel re- developed that exhibit genetic variations in their ceptor complex may be involved in mediating the sensitivity to the reinforcing effects of drugs of reinforcing actions of ethanol that promote alco- abuse and in their drug-seeking behavior (28). In hol drinking behavior in these rats. The observa- addition, genetic differences in various biological tion that RO 15-4513 blocks oral self-adminis- and neurochemical mechanisms have been ob- tration of alcohol supports this idea (56,108). served in these animals. Furthermore, treatment with a drug that activates For example, strains of rats and mice that differ the GABAA receptor was shown to markedly in their sensitivity to the reinforcing properties of increase the acquisition of voluntary ethanol cocaine and in their cocaine-seeking behavior consumption in laboratory rats (123). Also, have also been observed to have differences in the

GABAA receptor function is enhanced by alcohol number of dopamine containing neurons and in animals selected for sensitivity to alcohol receptors in certain brain areas (120). While the intoxication, but alcohol has little effect on role of these biological findings in the expression

GABAA receptors of animals selected for resis- of the behavioral traits is unclear, given that tance to alcohol intoxication (28). Overall, these dopamine is the key neurotransmitter in cocaine’s results are consistent with the involvement of the action, it is likely that a link may exist. Other

GABAA receptor in regulating alcohol consump- studies have shown that the development of tion. (See also ch. 3). nicotine tolerance is genetically related. Strains of Chapter 4-Genetics | 49

mice that differ in the rate at which they develop while the AZ allele is found in the remaining 80 tolerance to nicotine have also been found to percent (l). Two separate studies (9,10) reported differ in nicotine receptor changes following that the frequency of the Al allele for the D2 chronic administration of the drug (72). Thus, dopamin e receptor was significantly greater in inherited differences in nicotine receptor mecha- severe alcoholics compared with nonalcoholics. nisms may underlie inherited differences in the Furthermore, another study (88) found that indi- development of nicotine tolerance. viduals with the Al allele had fewer D2 receptors A recent study indicates that inherited differ- than those with the A2 allele. In agreement with ences in the intracellular mechanisms of the these findings, another study (91) observed a neurons in the mesocorticolimbic pathway could significant association between the Al allele of contribute to a genetic predilection to drug the D2 receptor and alcoholism. An association of addiction (87). In a comparison of rats with either the Al allele with alcoholism and decreased high or low rates of self-administering drugs of numbers of D2 dopamin e receptors implies a role abuse, the higher self-administering strain exhib- for an inherited deficit in the dopamine system in ited differences in the intracellular mechanisms alcoholism. However, in contrast to these results, that control activity in the neurons of the ventral other studies have not found an association tegmental area and nucleus accumbens (5). between the frequency of the Al allele of the D2 The further examination of causative relation- receptor and alcoholism (13,26,40,1 19). The dis- ships between inherited neurochemical altera- crepancies between these studies has called into tions and inherited behavioral traits would pro- question the validity of the association of the Al duce valuable information about the biological allele with alcoholism. mechanism that underlies genetic factors related Moreover, the report of a higher prevalence of to substance abuse and addiction. The recent the Al allele not only in alcoholics, but also in development of new and more sensitive tech- other disorders such as autism, attention deficit niques to analyze brain activity and processes will hyperactivity disorder, and Tourette’s syndrome facilitate such studies. (25), suggests that the presence of the Al allele is not specific for alcoholism, but that it has a more I Linkage Studies diffuse effect that can contribute to the occurrence Genetic linkage studies establish an associa- of other conditions. Also, recent findings indicate tion between an area of a specific chromosome that the frequency of the Al allele varies mark- and the expression of a trait. Linkage analysis edly among different populations (e.g., it is high uses specific markers that identify the area on a in some Native Americans) but there does not chromosome that might contain the gene of appear to be an association with its increased interest. If the marker consistently occurs in frequency and the occurence of alcoholism (43). association with the expressed trait, then it is This complexity, coupled with the heterogeneous likely that the gene interest is in chromosomal and complex nature of alcoholism, could account region. for the disagreements among these studies. Such In the area of substance abuse and addiction, complexity makes construction of appropriate genetic linkage studies have purported to show a control groups difficult, which in turn can affect linkage between the gene for the dopamine D2 study results. Additional research is needed to receptor and alcoholism. The gene for the D2 unravel the disagreement and establish the impor- receptor has two forms associated with two tance of these findings. It might be that the markers, the A 1 and A2 alleles. The Al allele presence of the Al allele is not unique to occurs in about 20 percent of the population, alcoholism, but rather, causes a general alteration 50 I Biological Components of Substance Abuse and Addiction

in the brain dopamine system that then exacer- Findings with animals selectively bred for alco- bates or contributes to alcohol abuse. hol preference need to be extended to studies of sensitivity, tolerance, and preference for other SUMMARY drugs of abuse. Neurobiological evidence points to common The existence of heritable influences on normal pathways mediating the positive reinforcing ac- and pathological consumption of alcohol is sup- tions of alcohol and other drugs of abuse. Most ported by results from family studies, twin evidence is consistent with the involvement of the studies, and adoption studies as well as research mesocorticolimbic dopamine system in drug rein- on animal models. Animal studies have estab- forcement mechanisms. Other neuronal pathways lished that alcohol preference and the reinforcing that regulate the activity of the mesocorticolimbic actions of alcohol are influenced by genetic dopamine system may also be involved in mediat- factors. While there have been fewer studies ing the rewarding properties of ethanol and other examining the genetic component of vulnerabil- drugs of abuse. In the case of serotonin, innate, ity to the addictive properties of other drugs of genetically determined factors appear to reduce abuse, evidence from animal studies supports a CNS activity of serotonin, which is associated genetic influence on the use and abuse of drugs with heavy alcohol drinking. In addition, animal other than alcohol. The study of nonalcohol drug and human studies suggest an inherited difference abuse in humans is more difficult because of in dopamine response to alcohol consumption substantially smaller populations that use or and possibly an anomaly in the D receptor for abuse these drugs and marked changes in availa- 2 Dopamine associated with alcohol abuse. Addi- bility and, hence, exposure to these agents. Investigation in this area is further hampered by tional studies with animals and humans are the complexity of subjects’ drug use: Most drug needed to clarify these differences and to explore abusers have used multiple agents. This has led the relationship of other neurobiological mecha- researchers either to concentrate on one class of nisms related to the inherited components of other drug or to treat all illicit drug use as equivalent. drugs of abuse. The tendency to lump all illicit drugs into one Alcoholism and drug abuse are complex condi- category makes results difficult to interpret or tions that are the result of multiple causal factors. compare. Alcoholism and other forms of addiction repre- In the case of alcohol, studies indicate that low sent entities that have a genetic component but doses of alcohol are stimulating and produce a require specific (but as yet poorly understood) strong positive reward in animals susceptible to environmental influences to manifest. Thus, con- the addictive properties of alcohol. Another sideration of the impact of genetic factors must component of excessive alcohol consumption also take into account general social conditions might be that alcoholics have a high threshold to such as availability and cost of substances, the aversive effects of ethanol. This could be a acceptability of use, and specific environmental result of an innate low sensitivity to medium and influences on initiation of use, maintenance or high doses of alcohol and/or acute tolerance to its cessation of use, and development of use-related aversive effects. Results from animal studies problems. A major goal of addiction research in suggest an association between high alcohol clinical populations is to determine who is preference and acute tolerance to the medium-and vulnerable under what conditions. Understanding high-dose effects of ethanol. These animal exper- this interaction might lead to better prediction of iments need to be extended and consideration relapse as well as improved matching of patients should be given to related studies in humans. and treatments. Chapter 4-Genetics 151

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126. Suzdak, P. D., Glowa, J. R., Crawley, J.N., et al., anol Self-Administration,” P.W. Kalivas, and “A Selective Imidazobenzcxhaz“ epine Antago- H.H. Samson (eds.), The Neurobiology of Drug nist of Ethanol in the Rat,’ Science 234: and Alcohol AaUiction, Annals of the Amen”can 1243-1247, 1986. Academy of Sciences 654:220-241, 1992. 127. Tarter, R. E., Alterrnan, A. I., and Edwards, K. L., 133. Winokur, G., Reich, T, Rimmer, J., et al., “Vulnembility to Alcoholism in Men: A Behavior- “Alcoholism. III. Diagnosis and Familial Psy- Genetic Perspective,” Journal of Studies on chiatric Illness in 259 Alcoholic Probands,” Alcoholism 46:329-356, 1985. Archives of General Psychiatry 23:104-111, 128. Tarter, R. E., and Edwards, K., “Psychological 1970. Factors Associated With the Risk for Alcohol- 134. Wong, D.T, Threlkeld, P. G., Lumeng, L., et al., ism, ’ Alcoholism: Clinical and E~erimental “Higher Density of Seroton.in 1-A Receptors in Research 12:471480, 1988. the~PPoca’mPusandce~~ cortex of Al~ol- 129. Thomasson, H. R., Edenberg, H.J., Crabb, D.W., Preferring Rats,” Life Sciences 46:231-235, et al., “Alcohol and Aldehyde Dehydrogenase 1990. Genotypes and Alcoholism in Chinese Men,” 135. Yoshida, A., “Genetic Polymorphisms of Alco- American Journal of Human Genetics 48:677- hol Metabolizing Enzymes and Their Signifi- 681, 1991, cance for Alcohol-Related Problems,” T.N. 130. Virkkunen, M., and Linnoila, M., “Serotonin in Palmer (cd.), Alcoholism: A Molecular Perspec- Early Onset, Male Alcoholics With Violent tive (New Yorlq NY: Plenum Press, 1991), Behavior,’ Annals of Medicine 22:327-331, 136. Yoshimoto, K., and McBride, W.J., ‘‘Regulation 1990. of Nucleus Accumbens Doparnine Release by 131. Virkkunen, M., Nuutila, A., Goodwin, F.K., et the Dorsal Raphe Nucleus in the Rat,” Neuro- al., ‘Cerebrospinal Fluid Monoamine Meta- chemistry Research 17:401407, 1992. bolizes in Male Arsonists,” Archives of General 137. Zhou, F.C,, Bledsoe, S., Lumeng, L., et al., Psychiatry 44:241-247, 1987. “Serotonergic Immunostained Terminal Fibers 132. Weiss, F., Hurd, YL., Ungerstedt, U., et al., Are Lower in Selected Forebrain Areas of ‘‘Neurochemical Correlates of Cocaine and Eth- Alcohol-Preferring Rats,” AZcohoZ 8:1-7, 1991. Appendix A: The Drug Evaluation Committee of the College on Problems of Drug Dependence

The Comprehensive Drug Abuse Prevention and input as requested in all NIDA decisions regarding the Control Act (PL 91-513) and the Psychotropic Sub- dependence potential of drugs. stances Act of 1978 (PL 95-633) gives exclusive Established in 1929, CPDD is the longest standing authority to the Secretary of the Department of Health group in the country concerned with drug dependence and Human Services to determine the abuse liability of and abuse. It is an independent body, affiliated with substances and to make recommendations concerning most scientific societies concerned with the depend- their regulation and other drug policy decisions. ence potential of abused substances and with regula- Although the Secretary receives advice from the Drug tory and governmental agencies such as the World Enforcement Agency (DEA), the Food and Drug Health Organization (WHO), MDA, the National Administration (FDA), and various other regulatory Institute on Alcoholism and Alcohol Abuse, DEA, and agencies, these laws explicitly state that the National FDA. Each of these agencies has formal ties with Institute on Drug Abuse (MDA) must provide to the CPDD via liaison membership. In turn, CPDD pro- secretary information relevant to the abuse potential of vides liaison representation to FDA and all other suspected drugs of abuse and all information relevant agencies on request. to an assessment of their abuse potential. On the basis CPDD has three major functions: to assess the abuse liability of psychoactive drugs; to hold an annual of this information from NIDA, and information from scientific meeting to review the status of the depend- FDA and DEA, the secretary makes a judgment as to ence liability of drugs; and, to seine as a consultant to the dependence potential of new drugs. the private sector and various governmental agencies NIDA’s role in providing information relevant to on all drug-related matters and policies. the dependence liability of potential substances of DEC oversees all aspects of CPDD’S dependence abuse has placed enormous demands on the Institute. liability testing program. DEC is devoted to research The agency supports a variety of activities in commer- on drugs of abuse and the determination of the cial and private laboratories around the country to dependence potential and abuse liability of specific provide this information. One of its principal sources classes of drugs: analgesics, stimulants, and depres- of information comes from the College on Problems of sants. Governmental and regulatory agencies, such as Drug Dependence (CPDD) and, specifically, its Drug NIDA, DEA, and FDA have relied on DEC for Evaluation Committee (DEC). The relationship be- information on the abuse liability of opiate-like tween NIDA and CPDD is both formal and informal: compounds and stimulant and depressant drugs, In NIDA provides over 98 percent of the funds required addition, CPDD is a collaborating center to WHO and to assess the dependence liability of compounds in provides information about the abuse potential of CPDD-sponsored testing facilities, NiDA is an official pharmaceuticals and scheduling worldwide. Produc- liaison member of CPDD, and CPDD provides direct ing this information is generally beyond the capabili- 59 60 I Biological Components of Substance Abuse and Addiction

ties of third world countries. Finally, CPDD provides Two university-based groups are involved with the pharmaceutical industry and academic investiga- DEC’S evaluation of the analgesic types of drugs, and tors information on new and novel compounds in the three with evaluation of the stimulants and depres- design and development phase. Thus, the information sants. The Medical College of Virginia, Virginia provided plays an important role in scheduling drugs, Commonwealth University, and the University of drug policy making decisions, and the facilitation of Michigan Medical School examine analgesics, using new drug development. different methods to discern the physical dependence Approximately 50 to 60 drugs per year are submit- potential and abuse liability of presumed analgesics. ted by industry, academic institutions, National Insti- Those two academic centers, along with the Missis- tutes of Health (NIH) laboratories, NIDA, WHO, and sippi Medical Center test stimulants and depressants. DEA (generally as a result of confiscation). A compu- ‘The programs’ testing determines dependence lia- terized list of submitted compounds is maintained at bility of drugs and, on request, carries out more NIH; the code is broken only when testing is complete detailed studies to examine specific aspects of depend- testing. ence liability, such as tolerance. For the last 30 years, Appropriate quantities of the compounds are distributed for testing to the various laboratories that this program has been largely responsible for obtaining work under the auspices of CPDD. The test results are basic scientific information on specific classes of released as soon as practical, but at most within 3 years compounds and the mechanisms involved in their of receipt of the compound. Information about the acute and chronic pharmacological effects. DEC drugs is confidential until one of three conditions is receives new compounds that are generally unavaila- satisfied: the submittee grants explicit permission to ble to other testing groups and provides scientific data release the data; 3 years have elapsed or, Federal on the pharmacology and abuse potential of new and/or regulatory organizations request CPDD to compounds. Thus the program contributes to the provide information concerning the compound for the development of new drugs and the understanding of public welfare (e.g., a determination of whether the the mechanisms underlying the abuse liability of compound should be scheduled under the Controlled drugs. Substances Act prior to its marketing and distribution to humans). Appendix B Acknowledgments

OTA thanks the members of the advisory panel, contractors, and the many individuals and organizations that supplied information for this report, In addition, OTA acknowledges the following individuals for their comments on drafts of this report:

Mary Abood Linda Dykstra Virginia Commonwealth University University of North Carolina Richmond, VA Chapel Hill, NC

Martin Adler R. Adron Harris Temple University School of Medicine University of Colorado Health Sciences Center Philadelphia, PA Denver, CO

Robert Balster Kenneth M. Johnson Virginia Commonwealth University University of Texas Medical Branch Richmond, VA Galveston, TX

Henry Begleiter William McBride State University of New York Institute of Psychiatric Research Brooklyn, NY Indianapolis, IN

John Crabbe Herman H. Samson Department of Veterans Affairs Medical Center Wake Forest University Portland, OR Winston-Salem, NC

Stephen Dinwiddie William Woolverton Jewish Hospital of St. Louis University of Mississippi Medical Center St. Louis, MO Jackson, MS

Stephen Dworkin Wake Forest University Winston-Salem, NC

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