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I I I I I I i I I I I I I I I I 10. DRUG ADDICTION AS A PSYCHOBIOLOGICAL PROCESS Michael A. Bozarth INTRODUCTION This chapter addresses the etiology of drug "addiction". The emphasis is on bioloeical mechanisms underlying "addiction", although some other factors influencing drug use will also be discussed. The presentation is limited primarily to psychomotor stimulants (e.g. amphetamine, cocaine) and opiates (e.g. heroin, morphine) for two reasons. First, considerable knowledge has been gained during the past 15 years regarding the neurobiological mecha- nisms mediating their use. Second, these two pharmacological classes represent the best examples of potent addictive drugs, and the elucidation of their "addiction potential" can provide a framework for understanding use and abuse to other psychotropic agents. Some psychologists and sociologists assert that animal studies do not model the important psychological variables governing drug use. They suggest that psychological processes critical in the etiology of use cannot bc studied in animal models and,•'or that environmental influences important in producing use cannot be duplicated in animal studies: T his position is generally untenable. and animal models have been developed that accurately represent the primary processes involved in drug "addiction". Support for the validity of these animal models will emanate from an understandina of the characteristics and the neural basis of drug use summarized in ~the following sections.The arguments presented in the chapter are tenable, but they represent only one of several perspectives used in studying substance use. The terminology and even some aspects of the empirical data are the topics of scientific debate. The objective of this chapter is not to provide a balanced presentation of controversial issues, but rather to develop a unifving framework for understanding the psychobiological basis of "addiction". CONCEPT OF ADDICTION Before proceeding with an examination of the mechanisms underlying drug addiction, it is necessary to define the term addiction and to examine its main characteristics. Delineation of the salient attributes of a phenomenon 112

I I I I I I I I I I 1 I I I I I I I Drug "Iddicrion as a Pst•cnodiological Process 113 helps to establish the criteria that must be fulfilled in a valid animal model and helps to determine what biological processes are relevant to its etiology. Issue of Terminology Drug addiction refers to a situation where drug procurement and administ- ration appear to govern the organism's behaviour, and where the drug seems to dominate the organism's motivational hierarchy. Jaffe (1975) has des- cribed addiction as "a behavioral pattern of compulsive drug use, characterized by overwhelming involvement with the usc of a drug, the sccuring of its supply, and a high tendcncy to relapse after withdrawal [abstinence]." (Jaffe, 1975: pp. 285) This definition follows the general lexical usage of the term and is consistent with the word's etymology (see Bozarth, 1987a). Drug addiction is defined behaviourally; it carries no connotations regarding the drug's potential adverse effects, the social acceptability of drug usage, or the physiological consequences of chronic drug administration (Jaffe, 1975). This latter point is especially important because some investi- gators have mistakenly used the term "addiction" to describe the develop- ment of physical dependence (see Bozarth, 1987a, 1989; Jaffe, 1975). Although drug addiction frequently has adverse medical consequences, it is usually associated with strong social disapproval, and it is sometimes accompanied by the development of physical dependence, these factors do not define addiction nor are they invariably associated with it. Drug addiction is an extreme case of compulsive drug use associated with strong motivational effects of the drug. Nature of Addiction Initial drug use can be motivated by a number of factors. Curiosity about the drug's effects, peer pressure, or psychodynamic processes can all provide sufficient motivation for experimental or circumstantial drug use. If the drue is taken repeatedly, a period of casual drug use often develops. Further use of the drug is associated with more frequent drug administration, the use of higher drug dosages, and/or the use of more effective routes of administ- ration (e.g. switching from intranasal to intravenous cocaine use) which can lead to intensive patterns of drug use. Continued, more sustained drug use can then produce compulsive drug use where the subst.ance has strong motivational properties and appears to govern much of the individual's behaviour. The most extreme case of drug use is the final progression to addiction. I

I I I I I I I I I I I I I I I I 114 hfichael A. Boz-arth Drug use is viewed as a continuum, progressine_ from casual u~,e to addiction (see :,ffe, 1975): the drug assumes increasing control of the individual's behaviour as the pattern of drug use approaches addiction. Jaffe (1975) suggests that addiction is an extreme case of drug use that is not qualitatively different, but rather quantitatively different, from compulsive drug use. The failur: to clearly distinguish between compulsive drug use and addiction appears to produce ambiguity and suggests a weakness in Jaffe's (1975) definitions of these terms. However, further consideration revcals that an important inference can be made regarding the nature of addiction. With this view, that drug addiction representing the extreme point on a continuum progressing from casual drug use, drug addiction does not represent a special situation, but rather an extreme case of behavioural control. The only change is in the drug's motivational strength and its disruption of the individual's normal motivational hierarchy. This latter effect has been termed motivational toxicity, (see Wise and Bozarth, 1985, for a discussion; see also Bozarth, 1989, and Johanson, Woolverton and Schuster, 1987). This represents a quantitative increase in the control of the individual's behaviour and not a qualitative shift in that behaviour. With this perspective, addiction is an exaggerated form of normal behaviour, similar to other types of psychopathology that represent extreme forms of exaggerated (compulsive) behaviour. The distinguishing feature is the extreme motivational strength, involving otherwise normal behavioural mechanisms. Therefore, it is a fundamental mistake to assume that addiction is a special case of behavioural control. Acquisition and Maintenance Phases Drug addiction is frequently divided into two phases, acquisition and maintenance. This conceptual partition acknowledges that different factors may be involved in these two phases and that different degrees of drug- takino behaviour are associated with these phases. T he progression from the acquisition phase to the maintenance phase of addiction is not a quantal change, but rather it represents a shift in the importance of various factors that control the organism's behaviour along with an increase in the motivational st.*cngth of the drug-taking behaviour. A brief example illus- trates the utility of considering addiction as a two stage process. Prior to the first experience with a drug, the direct rewarding effects of drug administration are largely irrelevant in governing the individual's behaviour, except of course in that expectancies are developed from social interactions (e.g. media exposure, conversations with experienced users). Initiation of drug-taking behaviour is governed by intrapersonal and sociolo- gical variables such as curiosity about the drug's effects or peer pressure to try the drug. After initial exposure to the drug, pharmacological variables are relevant and will influence subsequent drug-taking behaviour. Intraperso- I c I

I I I I I I I I I I I I I I I I Experimcnta! Drug lise / Drug Addiction as a PsYchobiological Process 115 Ca.sual Intensive Compulsive Addiction Drug Use Drug Use Drug Use circumstantial Motivational Strength Drug Use Motivational Toxicity --. Figure t A continuum of drug use illustrating the progression from casual drug use to addiction. The acquisition phase of addiction may be viewed as beginning with casual use and progressing to the point where the addiction has fully developed (viz. Maintenance phase). The various terms used to punctuate this continuum are not clearly demarcated: rather, they serve as convenient labels describing varying degrees of drug-taking behaviour. Motivational strength is the determining factor in categorizing drug use. Motivational toxicity has not been considered as a defining characteristic of addiction, although it may be the most distinguishing feature. (Becausc motivational strength is difficult to clinically ascertain, addiction might be better defined .` the prevalence of motivational toxicity. This would permit a more uniform diagnosis of addiction.) Terms described on the continuum were suggested by Jaffe, 1975. nal and sociological factors are probably still important in determining continued drug use, but they are less significant as the potent rewarding effects are repeatedly experienced. At some point there is a shift in control from intrapersonal/sociological to pharmacological factors in governing drug-taking behaviour. This is concomitant with a marked increase in the motivational strength of the drug and with a progression from casual to compulsive drug use and ultimat,rIv to drug addiction. This may occur very rapidly for some drugs, such as heroin or free-base cocaine, and much more slowly for other drugs, such as alcohol. The division of addiction into two separate phases does not presume that different mechanisms are involved in each phase. Rather, the demarcation acknowledges the possibility of different mechanisms but, more importantly, emphasizes differences in the motivational strength between the acquisition and maintenance of addictive behaviour. As will be described later in the chapter, the same psychobiological process underlies both phases but additional variables are important in the acquisition of addiction. These other variables lose much of their influence as the addiction fully develops and as it becomes increasingly under the control of basic pharmacological mechanisms. Individual versus Unitarv Theories A primary issue in considering the etiology of drug addiction is whether addiction to various drugs represents different processes, each specific to a I

I I I I I I I I I I 1 I I I I I I 116 Michael A. Bo:arth particular drug type (i.e., individual theories), or whether some general mechanism underlies addiction to different pharmacological classes of drugs (i.e., unitary theory). A more extreme variation of the multiple theory approach might assert that the cause of addiction to even a single drug varies with each individual, thus necessitating unique theories for ever\ case of addiction. In this latter situation, the causal elements in addiction would emanate primarily frorn ps%chodynamic processes. and the addiction would be viewed as nothing more :han a specific instance of psychopathology. Treatment approaciies used for other types of psychopathology would be appropriate, and no specialized procedures for treating addiction qua addiction would be necessary. This position has not gained popularity, nor is it tenable. as evidenced by the g--neral. failure of psychoanalytical and traditional psychotherapeutic methods to effectively treat drug addiction. The possibility that addiction to different drugs invol•, es a common mechanism has attracted many investigators, althouoh most researchers confine their work to a single drug class. Attempts to identify underlying mechanisms common to various drug addictions do not presume that addictions to all classes of drugs are identical; there are obvious differences among addictions to different drugs, and even individual cases involving the same drLg can display marked differences. However, certain elements of addiction seem to be shared across distinctively different pharmacological classes, and these similarities provide the impetus for developing unifying theories of addiction. The unifying-theory orientation suggests a somewhat different approach to studying addiction than the individual-theories orientation. First, drugs that produce the strongest addiction might b-. studied initially-the best examples of drug addiction should provide the best vehicle for identifying the unde:lying mechanisms. Weaker drugs would be examined after the relevant psychobiological processes have been delineated for drugs producing a rapid and profo..nd addiction. Second, t;;^- commonalties among these drugs should be identified and examined, and the differences should be presumed initially to have little importance in determining their properties. The fact that one drug class produces signs of general behavioural stimulation and another drug class produces general behavioural sedation might be attributed to "side effects" of these drugs and not deemed important in understanding their use. (See Hindmarch and colleagues, this volume) Third, individual theories of addiction would be developed for different drugs only as conclusive evidence showed that the more general theory was not adequate. This principle of parsimony has been useful in resolving other, seemingly complicated phenomena into simpler conceptualizations. ~ ANIMAL MODELS n Several animal mc.:els of human drug addiction have been studied. Some al~ ~ ~ d ~ t~

I I I I I I I I I I I I I I I I I Drug Addiction ac a Psti-chobiological Process 117 involve the interaction of drugs with electrical activation of brain reward pathways, while others have studied the various behavioural and physiologi- cal effects of drugs (see Bozarth, 1987a,b). The most popular methods have focused on the ability of druss to directly control the animal's behaviour. This approach is consistent with the behavioural definition of addiction, and it has the strongest face validity of any animal model used to study human drug addiction. Using traditional operant psychology techniques, laboratory animals can be trained to self-administer many psychotropic drugs. Although animals will self-administer drugs by various routes of administ- ration (e.g. oral, intrac:.stric, intracranial), the intravenous self- administration method has gained the most widespread acceptance. Animals are surgically prepared with intravenous catheters and are tested for voluntary drug self-administration using traditional operant techniques (see Yokel, 1987). Typically, the subjects are tested in an operant chamber containing a lever; depressing the lever automatically delivers drug through an intrati•enous catheter. Experimental procedures have been developed that permit trsting of unrestrained, freely moving subjects. With this technique, normal animal behaviour (e.g. grooming, feeding and drinking) can be studied concurrently with intravenous drug self-administration. Some drugs control behaviour in a manner similar to conventional reinforcers (e.g. food and water) when drug administration is made con- tingent upon lever pressing (Johanson, 1978; Spealman and Goldberg, 1978; see also Fischman and Schuster, 1978). Most drugs that are abused by people are readily self-administered by laboratory animals, and drugs that are not used by people are generally not self-administered by animals (Deneau, Yanagita and Seevers, 1969; Griffiths and Balster, 1979; Griffiths, Brady and Bradford, 1979a; Weeks and Collins, 19S7; Yokel, 1987). Procedures used to study intravenous drug self-administration in laboratory animals have aL~o been applied to studying drug self-administration in humans (see Henningfield et al, 1987; Mello and Mendeison, 1987). Approximately 80 percent of the animals tested for intravenous cocaine or heroin self-administration learn to self-administer the drug under standard laboratory conditions (see Bozarth, 1989). No special training procedures or pre-existing conditions (e.g. food deprivation) are necessary for these drugs to serve as rewards in this experimental paradigm. If operant shaping techniques are used, this number approaches 100 percent. Some animals learn within several hours of exposure to the testing procedure, while others may require two or three weeks of exposure for several hours each day before reliable patterns of drug self-administration emerge. Animals tested under limited access conditions (namely, no limitations on the amount of drug administered per hour, but subjects can only self-administer drug for a limited number of hours each day, e.g. 2 to 12 hours daily) maintain good general health and show little or no disruption of food and water intake. I

I I I I I I I I I I I I i I I I 11F M:,Jcael A. Bo=arth Limited access testing is the procedure used most often in intravenous self- administration studies, and is associated with low subject morbidity and attrition. Testing cocaine under unlimited access conditions (i.e., continuous testing 24 hours per day) is accompanied by an extremely high subject mortality (90 percent subject loss within 30 days: Bozarth and Wise, 1985), it produces a rapid deterioration in the animal's health. For this reason, the unlimited access procedu-e has been used very infrequently, and all further discussion of this metho:; will be restricted to limited acces: conditions. Animals tested for intravenou~ asychomotor stimulant or opiate self- administration quickly develop stuz)le patterns of drug intake, where the average hourly drug intake is consistent both within and between experimen- tal sessions. The effect of changing the amount of drug administered with each injection (i.e., unit dose) is predictabie, and the substitution of saline for reinforcing drug produces a rapid extinction of lever-pressing bchaviour. The intravenous self-administration procedure has been used extensively to study the behaviour maintained by drugs serving as reinforcers and to study the neural basis of drug reward. NEURAL BASIS OF DRUG REWARD The majority of research investigating the neural mechanisms of motivation and reward has been conducted using laboratory animals. Although most scientists see no difficulty in generalizing from these studies to human neurobiology, brief mention of the applicability of these data is warranted. First and foremost is the recognition that there are obvious anatomical and physiological differences, but the major difference between laboratory rats (the mos: commonly used species) and primates 's in cortical development. These brain regions are involved primarily in cognitive pro::esses, such as learning and memory, speech, and fine motor control. The basic motivatio- nal substrates across mammalian species are probably very similar. The limited neurophysiological and pharmacological investigations that have been conducted in hut~:ans seem to confirm this notion of similar brain reward pathways (e.g. Heath, 1964). Second is the acknowledgement that motivational differences do exist, but that the most important difference between people and other species probably involves cognitive influences on these motivational mechanisms. These influences cannot be fully studied in animal models, but they probably exert their primary influence on initial drug-taking behaviour and have much less influence once intensive patt:rns of drug taking have developed. Psychomotor Stimulant Reward Brain dopamine systems have been the focus of considerable attention in I

I I I I I I I I I I I I I I I I I Drug Addiction as a Pst-chobiologica! Process 119 ventral tegmental area Figure 2 A schematic illustration of the neural elements mediating psychomotor stimulant and opiate addiction. The rewarding effects of these drugs involve activation of the ventral tegmental dopamine system. The doparninergic stimulation of postsynaptic target cells in the nucleus accumbens is the critical event enhanced by these two pharmacological classes. Repeated opiate administration ean also produce physical dependence by an opiate action at several brain sites, including the periaqueductal grey region. (Brain outline and cortical mass were adapted from Diamond er a!, 1985.) behavioural neurobiology. In particular, the ventral tegmental dopamine system appears to have an important role in motivated behaviour (see Bozarth, 1987c) and in some types of psychopathology. This dopamine system has its cell bodies located in the ventral tegmental area and sends its axonal projections to several brain regions (see Lindvall and Bjbrklund, 1974; Ungerstedt, 1971a), most notably the nucleus accumbens (see Figure 2). It receives neural inputs from many diverse brain sites and modulates neural activity in cortical and limbic areas. The component of neural transmission generally most sensitive to pharma- cological manipulations is synaptic activity. Neurotransmitters are released following the arrival of an action potential at -the presynaptic terminal and rapidly diffuse across the synaptic cleft to postsynaptic target cells. Once bound to their receptors, they can either facilitate or inhibit neural activity in these target neurons. Psychomotor stimulants strongly affect catecholami- nergic synaptic transmission (viz., neurons releasing dopamine or norepi- nephrine). Cocaine blocks the inactivation of dopamine by inhibiting its presynaptic reuptake (Heikkila, Orlansky and Cohen, 1975) thereby increas- ing the effect of synaptically released dopamine. Amphetamine blocks dopamine reuptake and also inhibits its degradation by monoamine oxidase I

I I I I I I I I I I 120 Alichael A. Bo_arth (Axelrod. 1970; Carlsson, 1970). Both actions produce a potent enhancement of dopaminergic neurotransmission (see White, this volume). Other neuro- transmitter systems are also affected by psychomotor stimulants (e.g. noradrenergic, serotonergic), but several studies have shown that enhance- ment of dopaminergic neurotransmission is critically involved in the reward- ing action of these drugs. Neuroleptic drugs, which block dopaminc receptors, disrupt the intrave- nous self-administration of psychomotor stimulants, while drugs blocking noradrenergic receptors are ineffective (de Wit and Wise, 1977; Yokel and Wise, 1975, 1976; see also Yokel, 1987). Lesions of the dopaminergic terminal field in the nucleus accumbens attenuate psychomotor stimulant self-administration (Lyness, Friedle and Moore, 1979; Roberts, Corcoran and Fibiger, 1977, 1980; see also Roberts and Zito, 1987), as do lesions of the dopamine-containing cell bodies in the ventral tegmental area (Roberts and Koob, 1982). These studies have used a selective neurotoxin that destroys only dop:-mine neurons and has no appreciable effect on the other neurons found in those areas. Self-administration procedures have been adapted so that animals can self-administer drug directly into restricted brain areas (see Bozarth, 1983, 1987d). Studies using this intracranial self- administration technique have shown that amphetamine (Hoebel et al, 1983) or dopamine (Dworkin, Goeders and Smith, 1986) injections administered directly into the nucleus accumbens are rewarding. These lines of evidence have firinly established a role of the ventral tegmental dopamine system in psychomotor stimulant reward. , Opiate Reward ` Opiates do not appear to affect dopaminergic synaptic activity directly but do stimulate dopamine neurons by an action at the cell body region in the ~ ventral tegmentum. Following opiate administration the neural activity of these dopamine neurons is increased (Gysling and Wang, 1983; Matthews and German, 1984). Action potentills generated at the cell body region are - conducted along the axon to the synaptic terminals in the nucleus accumbens ,* (see Figure 2). There they produce an impulse-coupled release of dopamine. The increased cell firing rates in the ventral tegmentum lead to an increased doparnine release in the nucleus accumbens (Di Chiara and Imperato, 1988; , Westerink, 1978; Wood, 1983). Both the action of opiates in the cell body  region (enhancing dopamine cell firing rates) and the action of psychomotor stimulants in the terminal region (enhancing doparninergic synaptic activity) ~ produce a net increase in dopaminergic neurotransmission in the nucleus ZND ~r accumbens. Different neural elements are involved, but an important neural ~ action is sh~,red by both classes of drugs (see White, this volume). ~ Dopamine-depleting lesions of the ventral tegmental area disrupt the ~ ~ acquisition of intravenous heroin self-administration (Bozarth and Wise, ~ ~ O ! 00 ~ I

I I I . I I I I I I I I I I I I Drug Addictian as a Psi•chnniologica/ Process 121 1986). The effects of neuroleptics on opiate self-administration have been difficult to interpret (see Bozarth, 1986; Wise, 1987; cf. Ettenberg et al, 1982), but conditioning studies have shown that neuroleptics block opiate reward (Bozarth and Wise, 1981a; Phillips. Spyraki and Fibiger, 1982). Animals will readily self-administer opiates directly into the ventral tegmen- tal area (Bozarth and Wise, 1981b; Van Ree and Dc Wied, 1980), and the rewarding action of these injections has been confirmed using other beha- vioural techniques (Bozarth and Wise, 1982; Phillips and LePiane, 1980). The anatomical zone where morphine infusions are rewarding corresponds closely to the location of the dopamine-containing cell bodies in the ventral tegn;ental area (see Bozarth, 1987e). Infusions of morphine directly into the ventral tegmentum do not produce physical dependence, while morphine infusions into the periaqueductal gray region does produce physical depen- dence and is not rewarding (see Figure 2), (Bozarth and Wise, 1984). This neuroanatomical dissociation of reward and physical dependence shows that opiates can be rewarding without the development of physical dependence. The interpretation of research identifying the neural basis of opiate reward has been somewhat controversial, but considerable data suggest that opiates can activate the same brain reward system as that mediating reward from psychomotor stimulants. Direct support for this hypothesis comes from a study showing that ventral tegmental morphine injections can partially substitute for intravenous cocaine injections (Bozarth and Wise, 1986). This would be expected if the same brain reward system is critically involved in the rewarding actions of these two classes of drugs. In addition, chronic opiate administration may evoke other reward processes that are not shared with psychomotor stimulants, but these processes are not important in the initial rewarding action of opiates. Other Substance Use Other drugs may activate the ventral tegmental dopamine system; alcohol and nicotine have been shown to increase dopamine release in the nu accum ens Di Chiara and lmperato, 1988). The importance of this effect for the rewardin¢ actions of these com ounds has not been s stematicallv evaluated, but it is possi e that at least part of their use may be ex lained y an a=on on this reward system. Furthermore, the rewarding effect of electrical brain sttmu ation (at least from some electrode sites) appears to involve dopaminergic neurotransmission (Fibiger, 1978; Fibiger and Phillips, 1979; Wise 1978; see also Bozarth, 1987c), and the regulation of food and water intake has an important dopaminergic component (see Ungerstedt, 1971b; Wise, 1982). These data suggest that the ventral tegmental dopamine system may provide a general motivational function, and this hypothesis is consistent with the notion that drugs derive their rewarding effects by pharmacologically activating the brain reward systems which are involved in I