3: the Neuropharmacology of Drugs of Abuse

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 ulti- mately 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

CHAPTER 3 REFERENCES chopharmacology: The Third Generation (New 1. Abbott A., and Concar, D., “A Trip Into the York, NY: Raven Press, 1987). Unknown,” New Scientist, pp. 30-34, Aug. 29, 12. Caine, S. B., and Koob, G. F., “Modulation of 1992. Cocaine SeM-Adrninistration in the Rat Through 2. Abood, M.E., and Martin, B.R., “Neumbiologyof D-3 Doparnine Receptors,” Science 260:1814- Marijuana Abuse,” Trends in Pharmacological 1816, 1993. Sciences 13:201-206, 1992. 13. Carrel, M.E., “PCP and Hallucinogens,” Ad- 3. Agahjanian, G. K., Sprouse, J. S., and Rasmussen, vances in Alcohol and Substance Abuse 9:167- K., “Physiology of the Midbrain Serotonin Sys- 190, 1990. tem,” H. Y Meltzer (cd.), Psychophurrnacology: 14. Childers, S.R., Fleming, L., and Konkoy, C., The Third Generation (New York NY: Raven “Opioid and Cannabinoid Receptor Inhibition of %SS, 1987). Adenylyl Cyclase in Bmin,” P.W. Kalivas, and 4. Balfour, D.J.K., “The NeurochemicaJ Mecha- H.H. Samson (eds.), The Neurobiology of Drug nisms Underlying Nicotine Tolerance and De- and Alcohol Addiction, Annals of the American pendence,” J. Pratt (cd.), The Biological Basis of Acaakmy of Sciences 654:33-51, 1992. Drug Tolerance and Deperu&=wce (lmndon: Aca- 15. Cox, B. M., and Werling, L. L., “Opioid Tolerance demic Press, 1991), and Dependence,” J. Pratt (cd.), The Biological 5. Ballenger, J., Goodwin, F., Major, L., et al., Basis of Drug Tolerance and Dependence (Ixm- “Alcohol and Central Serotonin Metabolism in don: Academic Press, 1991). Man,” Archives of General Psychiatry 36:224- 16. Devane, W. A., Dysarz, F. A. I., Johnson, M, R,, et 227, 1979. al., “Determination and Characterization of a 6. Balster, R. L., “The Behavioral Pharmacology of Cannabinoid Receptor in Rat Brain,” MoZecular Phencyclidine,” H. Y. Meltzer (cd.), Psychophar- phannaco~o~ 34:605-613, 1988. macology: The Third Generation (New York, NY: 17. Devane, W.A., ‘‘Isolation and Structure of a Brain Raven Press, 1987). Constituent That Binds to the Cannabinoid Re- 7. Balster, R.L., “Drug Abuse,” L,B. Wingard, Jr., ceptor,” Science 258:1946-1948, 1992. T.M. Brody, J. Lamer, et al. (eds.), Human 18. Di Chiara, G., and North, R. A., “Neurobiology of Pharmacology (St Louis, MO: Mosby Year Book Opiate Abuse,” Trends in Pharmacological Sci- 1991). ences 13:185-193, 1992. 8. Balster, R. L., “Neurobehavioral Basis for the 19. File, S.E., “The History of Benzodiazepine De- Abuse of Cannabis, Phencyclidine, and Inha- pendence: A Review of Animal Studies,’ Neuro- lants,” International Research Conference on science & Biobehavioral Reviews 14:135-146, Biomedical Approaches to Illicit Drug Demand 1990. Reduction, Sea Island, Georgia, February, 1992. 20, Ford, M., et al., “Opioids and Designer Drugs,” 9. Balster, RL., “Delta-9-TetrahydrocannabinolDis- Emergency Medicine Clinics of North America crirnination in Rats as a Model for Cannabis 8(3):480-565, 613427, 1990. Intoxication,’ Neuroscience & Behavioral Re- 21. Gallager, D.W., Marley, R. J., and Hemandez, views 16:55-62, 1992. T.D., “Biochemical and Electmphysiologiml Mech- 10. Beitner-Johnson, D., Guitart, X., and Nestler, E.J., anisms Underlying Benzodiazepine Tolerance “Common Intracellular Actions of Chronic Mor- and Dependence,” J. Pratt (cd.), The Biok~gicaZ phine and Cocaine in Doparninergic Brain Re- Basis of Drug Tolerance and Dependence @xm- ward Regions, ” P,W. Kalivas, and H.H. Samson don: Academic Press, 1991). (eds.), The Neurobiology of Drug and Alcohol 22. Gardner, E.L., and I..owinson, J. H., “Marijuana’s Ackh”ction, Annals of the American Academy of Interaction With Brain Reward Systems: Update Sciences 654:70-87, 1992. 1991,” Pharmacology, Biochemistry & Behavior 11. Bowers, M. B., “l’he Role of Drugs in the 40:571-580, 1991. Production of Schizophreniform Psychoses and 23. Gold, L.H., Balster, R. L., Barrett, R.L., et al., “A Related Disorders,” H. Y Meltzer (cd.), Psy- Comparison of the Discriminative Stimulus Prop- —

Chapter 3-The Neuropharmacology of Drugs of Abuse 137

erties of Delta-9-THC and CP 55,940 in Rats and the Nucleus Accumbens Is Associated With Rhesus Monkey s,’ Journal of Pharmacology and Alcohol Preference in Rats,” AZcohoZism 14:503- Experimental Therapeutics 262:479-486, 1992. 507, 1990. 24. Grant, K.A., Valverius, P., and Hudspith, M., 35, Insthute of Medicine, Marijuana and Health “Ethanol Withdrawal Seizures and NMDA Re- (Washington, D. C., National Academy Press, ceptor Complex, ’ European Journal of Pharrna - 1982). coio~ 176:289-2%, 1990. 36. Jaffe, J.H., “Drug Addiction and Drug Abuse,” 25. Griffiths, R. R., and Sannerund, C. A., “Abuse of A.G. Gilrnan, TW. Rail, A.S. Nies, et al. (eds.), and Dependence on Benzodiazepines and Other The Pharmacological Basis of Therapeutics (New Anxiolytic/Sed.ative Drugs,” H. Meltzer (cd.), York NY: Pergamrnon Press, 1990). Psychopharmacology; The Third Generation of 37. Johnson, K.M., “The Neurochernical Pharmacol- Progress (New York, NY: Raven Press, 1987). ogy of Phencyclidine,” H. Meltzer (cd.), Psy- 26. Harnon, M., “Common Neurochernical Cone- chopharmacology: The Third Generation of Prog- lates to the Action of Hallucinogens,” B. Jacobs ress (New York, NY: Raven Press, 1987). (cd.), Hallucinogens: Neurochemical, Behavioral 38. Jones, R.T, “Tobacco Dependence,” H. Meltzer and Clinical Perspectives (New Yorlq NY: Raven (cd.), Psychopharmacology: The Third Genera- PRSS, 1984). tion of Progress (New York, NY: Raven Press, 27. Harris, R. A., Brodie, M. S., and Dunwiddie, TV., 1987). “Possible Substrates of Ethanol Reinforcement: 39. Koob, G.F., ‘Drugs of Abuse: Anatomy, Pharma- GABA and Doparnine,” P.W. Kalivas and H.H. cology, and Function of Reward Pathways,’ Samson (eds.), The Neurobiology of Drug and Trend in Pharmacological Sciences 13:177-184, Alcohol Addiction, Annals of the American Acad- 1992. emy of Sciences 654:61-69, 1992. 40. Koob, G. F., “Neural Mechanisms of Drug Rein- 28. Heishman, S.J., and Henningfield, J, E., “Stimulus forcement,’ P.W. Kalivas, and H.H. Samson Functions of Caffeine in Humans: Relation to (eds.), The Neurobiology of Drug and Alcohol Dependence Potential,’ Neuroscience and Biobe - Adalction, Annals of the American Academy @ havioral Reviews 16:273-287, 1992. Sciences 654:171-191, 1992. 29. Herkenharn, M., ‘‘Cannabinoid Receptor localiz- 41. Koob, G. F., and Bloom, F. E., “Cellular and ation in Brain: Relationship to Motor and Reward Molecular Mechanisms of Drug Dependence, ” Systems,” P.W. Kalivas and H.H. Samson (eds), Science 242:715-723, 1988. The Neurobiology of Drug and Alcohol Addiction, 42. Lett, B. T., “Repeated Exposures Intensify Rather Annals of the American Academy of Sciences Than Diminish the Rewarding Effects of Amphet- 654:19-32, 1992. amine, Morphine, and Cocaine,’ Psychopharrna - 30. Herkenham, M., Lynn, A. B., Little, M.D., et al., co[o~ 98:357-362, 1989. “Cannabinoid Receptor bdization in Brain,” 43. Little, H.J., “Ethanol Tolerance and Physical Proceedings of the National Academy of Sciences Dependence: The Role of Calcium Charnels and 87:1932-1936, 1990. Other Possible Mechanisms,” J. Pratt (cd.), The 31. Hollister, L. E., “Effects of Hallucinogens in Biological Basis of Drug Tolerance and Depend- Humans, ” B. Jacobs (cd.), Hallucinogens: Neu- ence (hmdon: Academic Press, 1991). rochemical, Behavioral and Clinical Perspectives 44. Mello, N.K., “A Behavior Analysis of the Rein- (New York, NY: Raven Press, 1984). forcing Properties of Alcohol and Other Drugs in 32. Hollister, L. E., “Health Aspects of Cannabi- Man,” B. Kissin, and H. Begleiter (eds.), The noids,” Pharmacological Review 38:1-20, 1986. Biology of Alcoholism: The Pathogenesis of 33. Holzman, S. G., “Caffeine as a Model of Drug Alcoholism (New York, NY: Plenum Press, Abuse,’ Trends in Pharmacological Science 1983), 11:355-356, 1990. 45. Miller, N. S., The Pharmacology of Alcohol and 34. Hwang, B. H., Lumeng, L., Wu, J. Y., et al., Drugs of Abuse and Addiction (New York, NY: “Increased Number of GABAergic Terminals in Springer-Verlag, 1991). 38 I Biological Components of Substance Abuse and Addiction

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.