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Recent Advances in Animal Models of Drug Addiction

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Recent Advances in Animal Models of Drug Addiction 97 RECENT ADVANCES IN ANIMAL MODELS OF DRUG ADDICTION TONI S. SHIPPENBERG GEORGE F. KOOB DEFINITIONS AND VALIDATION OF butes of a drug (e.g., pleasure) that cannot be easily defined ANIMAL MODELS operationally. This chapter reviews animal models currently used to Definitions of Drug Addiction examine the neurobiological basis of drug addiction and the Drug addiction is defined as a compulsion to take a drug role of reinforcement processes in its initiation, mainte- with loss of control in limiting intake (33). It is considered nance, and reinstatement. Emphasis is place on more re- a chronic disorder because the risk of relapse remains high cently developed models, and where possible, the models even after completion of treatment and prolonged absti- are evaluated in terms of reliability and predictability to nence. In 1968, the term drug dependence replaced that of the human condition. Potential pitfalls to consider when addiction in the nomenclature of the World Health Organi- interpreting data also are discussed. zation and the American Psychiatric Association. Defined as a cluster of cognitive, behavioral, and physiologic symptoms ANIMAL MODELS OF THE POSITIVE indicative of an individual continuing substance use despite REINFORCING EFFECTS OF DRUGS significant substance related problems, this term has become the accepted diagnostic term for compulsive use of a psy- Drugs of abuse function as positive reinforcing stimuli; this choactive substance. When defined as described, it is analo- action has provided the framework for currently used animal gous to the term addiction. However, this term should not models of addiction. It is also clear that humans and experi- be confused with physical or psychic dependence, condi- mental animals will readily self-administer these agents in tions in which the cessation or reduction of drug usage the absence of a withdrawal state. Earlier models of drug results in a withdrawal syndrome. Withdrawal and tolerance reinforcement used operant paradigms in nonhuman pri- often are associated with compulsive drug use; however, mates; however, many of these same paradigms now are they are not required for drug addiction. Although individu- utilized in rodents. The use of these rodent models, together als suffering from chronic pain may develop tolerance to with the development of modern neurobiological tech- the analgesic effects of an opiate and experience withdrawal niques, has provided important information regarding the symptoms, they do not exhibit signs of compulsive drug- neurobiology of addiction (11,15,36,45,51). seeking behavior. The concept of reinforcement has provided the corner- Operant Intravenous Drug stone for current theories and animal models of drug addic- tion. A reinforcer is defined operationally as ‘‘any event that Self-Administration increases the probability of a response’’ and often is used Drugs of abuse are readily self-administered intravenously interchangeably with ‘‘reward.’’ In general, drugs function by experimental animals, and, in general, drugs that are as positive or conditioned reinforcers by virtue of their re- self-administered correspond to those that have high abuse warding effects, and reward often connotes additional attri- potential. However, that not all drugs abused by humans are self-administered by experimental animals (e.g., halluci- nogens). Furthermore, there are species- and strain-related differences in the degree to which a drug is self-administered Toni S. Shippenberg: National Institutes of Health, National Institute (48,62). A detailed review of intravenous self-administra- on Drug Abuse, Bethesda, Maryland. George F. Koob: Department of Neuropharmacology, The Scripps Re- tion was presented in the previous edition (46); therefore, search Institute, La Jolla, California. only key points are presented here. 1382 Neuropsychopharmacology: The Fifth Generation of Progress For intravenous self-administration studies, the subject for assessment of drug seeking in the absence of drug admin- acquires a drug infusion by performing a discrete response. istration. The number and pattern of responding required for each infusion is determined by the schedule of reinforcement Multiple Schedules imposed by the experimenter. Drug availability typically is signaled by an environmental stimulus. The dependent Clinical definitions of drug addiction and dependence typi- variables are the number of infusions obtained or the rate cally refer to the disruptive effects of addiction on of responding during a session. In addition to the intrave- non—drug-related activities. The use of multiple schedules nous route of administration, the intragastric or oral route of reinforcement enables the application of concepts of be- can be employed (see the following). havioral economics (e.g., commodities, consumption, price, and demand) to operant behavior. It also can provide a control for nonselective effects of drug reinforcement. In Simple Schedules these procedures, self-administration of a drug is incorpo- In fixed-ratio schedules, the number of responses required rated into a multiple component schedule with other rein- for drug infusion is set at a fixed number. In rodents, these forcers. Studies using these procedures have shown that the schedules generally will not maintain stable responding contingencies for concurrent reinforcers can affect behavior below a certain unit dose and, within the range of doses asymmetrically and that the response requirement for rein- that maintains stable responding, self-administration rate is forcers can affect drug self-administration (12). Drugs also inversely related to dose. Within the range of doses that can function as substitutes for, complements of, or be inde- maintains stable responding, animals increase their self- pendent from, the ‘‘price’’ of one another and can be inter- administration rate as the unit dose is decreased. Conversely, preted in economic terms. In addition to evaluating the animals reduce their rate of self-administration as the unit selectivity of manipulations that apparently reduce the rein- dose is increased. In a fixed-interval schedule, the frequency forcing efficacy of a drug, these procedures can provide in- of injections is determined primarily by the interval sched- formation regarding those factors affecting ‘‘loss of control,’’ ule imposed and not the response rate. Therefore, the use as well as behavioral and/or pharmacologic therapies for the of these two schedules can provide information regarding treatment of addiction. Behavior maintained by alternate both the motivational effects of a drug and potential non- presentation of natural reinforcers (e.g., food and water) specific motor effects that can confound data interpreta- and drugs of abuse in the same session and with the same tion. reinforcement requirements has been reported for several species (16,20,97,98). Progressive-Ratio Schedules Second-Order Schedules Progressive-ratio schedules are used to evaluate the reinforc- In a second-order schedule, completion of an individual ing efficacy of a self-administered drug. In this procedure component (or part) of the schedule produces the terminal the response requirements for each successive drug rein- event (drug infusion) according to another overall schedule. forcement are increased and the breaking point (the point Typically, completion of a unit schedule results in the pre- at which the animal will no longer respond) is determined sentation of a brief stimulus, and completion of the overall (89). Breaking points are defined either as the largest ratio schedule results in the delivery of the stimulus and the drug. requirement that the subject completes or as the number Second-order schedules have the advantage that they main- of ratios completed by the subject per session. This value tain high rates of responding and extended sequences of represents the maximum work a subject will perform to behavior before any drug infusion occurs. Therefore, acute receive an infusion of a drug. Because the dependent mea- drug effects on response rates are minimized. High response sure in progressive-ratio schedules is not directly related to rates are maintained even for doses that decrease rates when the rate of responding, interpretive problems associated with several injections are self-administered during a session (43). using rate of responding as a measure of reinforcement effi- In addition, this schedule requires extended sequences of cacy are avoided. behavior, thus, modeling the human condition in which This schedule has been used to study the relative reinforc- drug taking is preceded by a series of behaviors (e.g., pro- ing efficacy of compounds both within and across drug curement, preparation). Although second-order schedules classes (61) as well as the neural basis of drug reinforcement are more typically used in nonhuman primate studies of (58,61,78,89). Drug craving has been conceptualized as the addiction, their use in rodents is increasing (8,55,73). incentive motivation to self-administer a drug that has been previously consumed; therefore, this schedule can also pro- Oral Drug-Self Administration vide an animal model of drug craving. However, the break- ing point reflects both the unconditioned (reinforcing) and Oral self-administration has focused largely on alcohol be- conditioned incentive effects of drugs and does not allow cause of the obvious face validity of oral alcohol self-admin- Chapter 97: Recent Advances in Animal Models of Drug Addiction 1383 istration and
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