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psych Drug Addiction as a Psychobiological Process The emphasis is on biological mechanisms underlying addiction, although some other factors influencing drug addiction 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 mechanisms mediating their addictive properties. 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 abuse and addiction to other psychotropic agents. Some psychologists and sociologists assert that animal studies do not model the important psychological variables governing drug addiction. They suggest that psychological processes critical in the etiology of addiction cannot be studied in animal models and/or that environmental influences important in producing an addiction cannot be duplicated in animal studies. This 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 understanding of the characteristics and the neural basis of drug addiction summarized in the following sections. The arguments presented in the chapter are tenable, but they represent only one of several perspectives used in studying addiction. 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 unifying 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 the main characteristics of drug addiction. Delineation of the salient attributes of addiction helps to establish the criteria that must be fulfilled in a valid animal model and helps to determine what biological processes are relevant to the etiology of addiction. Issue of Terminology Drug addiction refers to a situation where drug procurement and administration appear to govern the organism’s behavior, and where the drug seems to dominate the organism’s motivational hierarchy. Jaffe (1975) has described addiction as "a behavioral pattern of compulsive drug use, characterized by overwhelming involvement with the use of a drug, the securing of its supply, and a high tendency to relapse after withdrawal [abstinence] (p. 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 behaviorally. 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 investigators have mistakenly used the term addiction to describe the development 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 drug is taken repeatedly, a period of casual drug use often develops. Further use of the drug associated with more frequent drug administration, the use of higher drug dosages, and/or the use of more effective routes of administration (e.g., switching from intranasal to intravenous cocaine use) can lead to intensive patterns of drug use. Continued, more sustained drug use can then produce compulsive drug use where the substance has strong motivational properties and appears to govern much of the individual’s behavior. The most extreme case of drug use is the final progression to addiction. Drug use is viewed as a continuum, progressing from casual use to addiction (see Jaffe 1975); the drug assumes increasing control of the individual’s behavior 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 failure 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. Further consideration, however, reveals that an important inference can be made regarding the nature of addiction. With this view—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 behavioral 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 et al. 1987). This represents a quantitative increase in the control of the individual’s behavior and not a qualitative shift in that behavior. With this perspective, addiction is an exaggerated form of normal behavior, similar to other types of psychopathology that represent extreme forms of exaggerated (compulsive) behavior. The distinguishing feature is the extreme motivational strength involving otherwise normal behavioral mechanisms. Therefore, it is a fundamental mistake to assume that addiction is a special case of behavioral 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-taking behavior are associated with these phases. The 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 behavior along with an increase in the motivational strength of the drug-taking behavior. A brief example illustrates 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 behavior, except of course in that expectancies are developed from social interactions (e.g., media exposure, conversations with experienced users). Initiation of drug-taking behavior is governed by intrapersonal and sociological 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 behavior. Intrapersonal 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 behavior. 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 ultimately 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 behavior. 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 control of basic pharmacological mechanisms. Individual vs. Unitary Theories A primary issue in considering the etiology of drug addiction is whether addiction to various drugs represents different processes, each specific to a 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 every case of addiction. In this latter situation, the causal elements in addiction would emanate primarily from psychodynamic processes, and the addiction would be viewed as nothing more than a specific instance of psychopathology. Treatment approaches 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 general failure of psychoanalytical and traditional psychotherapeutic methods to effectively treat drug addiction. The possibility that addiction to different drugs involves a common mechanism has attracted many investigators, although 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 drug 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 does the individual theories orientation. First, drugs that produce the strongest addiction might be studied initially—the best examples of drug addiction should provide the best vehicle for identifying the underlying mechanisms. Drugs with weaker addictive properties would be examined after the relevant psychobiological processes have been delineated for drugs producing a rapid and profound addiction. Second, the commonalties among these addictive drugs should be identified and examined, and the differences should be presumed initially to have little importance in determining their addictive properties. The fact that one drug class produces signs of general behavioral stimulation and another drug class produces general behavioral sedation might be attributed to "side effects" of these drugs and not deemed important in understanding their addictive properties. 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 Several animal models of human drug addiction have been studied. Some involve the interaction of addictive drugs with electrical activation of brain reward pathways, while others have studied the various behavioral and physiological effects of drugs (see Bozarth 1987ab). The most popular methods have focused on the ability of drugs to directly control the animal’s behavior. This approach is consistent with the behavioral 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 administration (e.g., oral, intragastric, 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 intravenous catheter. Experimental procedures have been developed that permit testing of unrestrained, freely moving subjects. With this technique, normal animal behavior (e.g., grooming, feeding and drinking) can be studied concurrently with intravenous drug self-administration. Addictive drugs control behavior in a manner similar to conventional reinforcers (e.g., food and water) when drug administration is made contingent upon lever pressing (Johanson 1978; Spealman and Goldberg 1979; see also Fischman and Schuster 1978). Most drugs that are addictive in humans are readily self-administered by laboratory animals, and drugs that are not addictive in humans are generally not self-administered by animals (Deneau et al. 1969; Griffiths and Balster 1979; Griffiths et al. 1979a; Weeks and Collins 1987; Yokel 1987). Procedures used to study intravenous drug self-administration in laboratory animals have also been applied to studying drug self-administration in humans (see Henningfield et al. 1987; Mello and Mendelson 1987). Approximately 80% of the animals tested for intravenous cocaine or heroin self-administration learn to self-administer 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%. 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 (viz., 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. Limited access testing is the procedure used most often in intravenous self-administration studies, and it 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% subject loss within 30 days; Bozarth and Wise 1985), and it produces a rapid deterioration in the animal’s health. For this reason, the unlimited access procedure has been used very infrequently, and all further discussion of this method will be restricted to limited access conditions. Animals tested for intravenous psychomotor stimulant or opiate self-administration quickly develop stable patterns of drug intake, where the average hourly drug intake is consistent both within and between experimental sessions. The effect of changing the amount of drug administered with each injection (i.e., unit dose) is predictable, and the substitution of saline for reinforcing drug produces a rapid extinction of lever-pressing behavior. The intravenous self-administration procedure has been used extensively to study the behavior 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 primary difference between laboratory rats (the most commonly used species) and phylogenetically higher mammals is in cortical development. These higher brain centers are involved primarily in cognitive processes such as learning and memory, in speech, and in fine motor control. The basic motivational substrates across mammalian species are probably very similar. The limited neurophysiological and pharmacological investigations that have been conducted in humans 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 human and infrahuman animals 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 behavior and have much less influence once intensive patterns of drug taking have developed. Brain dopamine systems have been the focus of considerable attention in behavioral neurobiology. In particular, the ventral tegmental dopamine system appears to have an important role in motivated behavior (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 Bjorklund 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. Psychomotor Stimulant Reward The component of neural transmission generally most sensitive to pharmacological 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 catecholaminergic synaptic transmission (viz., neurons releasing dopamine or norepinephrine). Cocaine blocks the inactivation of dopamine by inhibiting its presynaptic reuptake (Heikkila et al. 1975) thereby increasing the effect of synaptically released dopamine; amphetamine blocks dopamine reuptake and also inhibits its degradation by monoamine oxidase (Axelrod 1970; Carlsson 1970). Both actions produce a potent enhancement of dopaminergic neurotransmission. Other neurotransmitter systems are also affected by psychomotor stimulants (e.g., noradrenergic, serotonergic), but several studies have shown that enhancement of dopaminergic neurotransmission is critically involved in the rewarding action of these drugs. Neuroleptic drugs—which block dopamine receptors—disrupt the intravenous 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 et al. 1979; Roberts et al. 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 dopamine 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 et al. 1986) injections administered directly into the nucleus accumbens are rewarding. These lines of evidence have firmly 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 potentials 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 dopamine 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 dopaminergic synaptic activity) produce a net increase in dopaminergic neurotransmission in the nucleus accumbens. Different neural elements are involved, but an important neural action is shared by both classes of drugs. Dopamine-depleting lesions of the ventral tegmental area disrupt the acquisition of intravenous heroin self-administration (Bozarth and Wise 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 et al. 1982). Animals will readily self-administer opiates directly into the ventral tegmental area (Bozarth and Wise 1981b; Van Ree and De Wied 1980), and the rewarding action of these injections has been confirmed using other behavior 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 tegmental area (see Bozarth 1987e). Infusions of morphine directly into the ventral tegmentum do not produce physical dependence, while morphine infusions into another brain site that does produce physical dependence (i.e., the periaqueductal gray region; see Figure 2) are not rewarding (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 Bibliography:

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