From M.A. Bozarth (1994). Opiate reinforcement processes: Reassembling multiple mechanisms. Addiction, 89, 1425-1435. [Tables have been omitted from this electronic version.]
This paper describes four putative motivational effects of opiates involving three motivational processes and two brain systems. Even so, this represents an over simplification of the complexity of opiate reward and its control of drug-taking behavior. Three of these components involve the ventral tegmental dopamine system and one involves the periventricular gray region.3 Two are positive reinforcement processes and two are negative reinforcement processes. Three of these actions are present only with chronic opiate administration.
One feature of addiction that has received relatively little attention is motivational toxicity. As addiction develops, interest in other, natural reinforcers (e.g., food, sex) diminishes and behavior becomes more focused on drug procurement and administration. Concomitant with increased motivational strength for drug-related behaviors is a severe attenuation of the motivational properties of other reinforcers. The organism's motivational hierarchy is thus disrupted as addiction develops, and even behaviors essential for the survival and well-being of the organism have less motivational significance. This has been termed motivational toxicity (Wise & Bozarth, 1985), and it may be a defining characteristic of drug addiction (Bozarth, 1990).
Most drugs that are addictive in humans can serve as reinforcers in other mammals. This fact suggests that addictive drugs act on brain circuitry common to all mammals and that operant conditioning procedures can be used to study the biobehavioral basis of addiction using laboratory animal models (see Bozarth, 1987). Furthermore, a primary action of many addictive drugs seems to involve pharmacological activation of brain systems governing normal behavior. Indeed, addictive drugs can be used as tools to study some basic motivational processes and their underlying biological mechanisms.
A single example will be used to illustrate this principle. This example addresses the dissociation of opiate reinforcement from the physical dependence-producing effects of opiates. This issue is of primary interest in the study of addiction, because physical dependence has been offered as an explanation (even a defining characteristic) of drug addiction. Separation of physical dependence from reinforcement mechanisms demonstrates that drug-taking behavior can be established and maintained without the usual concomitant development of physical dependence and the potential negatively reinforcing effects of subsequent drug intake. This has contributed to a major conceptual advance concerning the nature of drug addiction.
The reinforcing effect of opiates has been temporally, procedurally, neuroanatomically, and neurochemically dissociated from their physical dependence-producing effects. Conditioning studies have shown that a single injection of opiate is rewarding (Bozarth & Wise, 1983). Thus, with no opportunity for relief of withdrawal discomfort from repeated injections, reinforcement and physical dependence mechanisms are temporally dissociated. Intravenous self-administration studies have used low-dose, limited access schedules of testing that apparently preclude the development of physical dependence (e.g., Dai, Corrigall, Coen, & Kalant, 1989; Ternes, Ehrman, & O'Brien, 1985). Thus, opiate reinforcement can be demonstrated at low exposure levels procedurally dissociating reinforcement and physical dependence mechanisms. Opiate infusions directly into the ventral tegmental area are reinforcing but fail to produce physical dependence (Bozarth & Wise, 1983, 1984); opiate infusions directly into the periventricular gray region are not reinforcing in drug-naive subjects but produce physical dependence. Thus, different CNS sites of action neuroanatomically dissociate reinforcement and physical dependence mechanisms. Finally, neuroleptics appear to block the initial reinforcing action of opiates (Bozarth & Wise, 1981a; Phillips, Spyraki, & Fibiger, 1982), but these dopamine-receptor blockers have little effect on the development of physical dependence. Thus, reinforcement and physical dependence can be dissociated by their underlying neurochemical mechanisms.
The study of reinforcement mechanisms demands the use of intact animal preparations. In vitro models can be used to study presumed correlates of drug reinforcement (e.g., opiate receptor binding, activation of second messengers), but only behaving organisms can truly assess reinforcing effects. Through the use of various experimental manipulations, relative isolation of reinforcement mechanisms has been achieved in situ, and the independent contributions of various brain systems have been studied in freely behaving animals with considerable success.
The initial reinforcing effect of opiates involves activation of the ventral tegmental dopamine system. Opiate action at the ventral tegmentum is sufficient to produce reward (Bozarth & Wise, 1981b; Phillips & LePiane, 1980, van Ree & de Wied, 1980) and blocking opiate action in this brain region attenuates6 the reinforcing effect of systemically delivered opiate (Britt & Wise, 1983). Opiates have been shown behaviorally (Holmes, Bozarth, & Wise, 1983; Joyce & Iversen, 1979), electrophysiologically (Gysling & Wang, 1983; Matthews & German, 1984), and neurochemically (Di Chiara & Imperato, 1988; Westerink, 1978; Wood, 1983) to activate this dopamine system, and dopaminergic activity is essential for at least the initial rewarding effect of opiates (Bozarth & Wise, 1981a; Phillips et al., 1982). The most direct evidence of an essential role for the ventral tegmental dopamine system is the demonstration that destruction of the dopamine-containing cell bodies in the ventral tegmentum disrupts the acquisition of intravenous heroin self-administration (Bozarth & Wise, 1986).
These and numerous other studies argue for a critical role of the ventral tegmental dopamine system in the initial reinforcing action of opiates. This action involves an appetitive motivational process similarly activated by the psychomotor stimulants (Bozarth, 1986; Wise & Bozarth, 1987). Opiate activation of this system can also elicit other, natural behaviors such as feeding (Hamilton & Bozarth, 1988), maternal (Thompson & Kristal, 1992), and sexual (Mitchell & Stewart, 1990) behaviors. This system is where opiates interface with a brain mechanism mediating appetitive motivation and reward (Bozarth, 1991; Wise & Bozarth, 1987), and the contribution to addiction made by this system probably involves the pharmacological activation of neural mechanisms involved in the control of normal behavior (see Bozarth, 1990; Wise & Bozarth, 1987). But all of these studies involve the short-term effects of opiates and all fail to consider the long-term actions of repeated opiate administration.
Some empirical support for a negative reinforcement mechanism related to opiate withdrawal has been obtained. Animals made physically dependent on opiates will lever press to avoid injections of a narcotic antagonist that precipitate withdrawal (Downs & Woods, 1973; Goldberg, Hoffmeister, Schlichting, & Wuttke, 1971). Animals develop conditioned place aversions to environmental stimuli associated with opiate withdrawal (Mucha, 1987). And narcotic antagonist microinjections into the periventricular gray region increase intravenous opiate self-administration (Corrigall & Vaccarino, 1988). These studies are consistent with the proposed motivational properties of withdrawal distress but do not demonstrate the importance of this mechanism in the control of drug-taking behavior.
The ventral tegmental dopamine system is tonically active, and the activity of this system may help regulate normal affective tone. If depressed dopaminergic activity in this system produces anhedonia and depression, natural rewards could lose much of their motivational impact (see Wise, 1982). The impaired ability of natural rewards to activate this system might produce a negative contrast effect further disrupting the ability of nondrug reinforcers to influence behavior. This reward devaluation could cause increased motivational focusing toward drug reinforcement and might be a fundamental factor in motivational toxicity. A similar depression in dopaminergic activity has been suggested as a factor in cocaine addiction (Dackis & Gold, 1985).
Empirical support for this mechanism comes the demonstration that termination of repeated opiate administration decreases dopaminergic activity in this system (Pothos, Rada, Mark, & Hoebel, 1991; Rossetti, Hmaidan, & Gessa, 1992). A similar decrease in dopaminergic activity has been noted following the termination of cocaine administration (Bozarth, 1989; Rossetti et al., 1992). And normal dopaminergic activity is restored with continued opiate intake (Rossetti et al., 1992). Although these studies reveal a depression in dopamine function following repeated opiate administration, they do not test the motivational properties of this effect nor do they establish that similar depressions are seen with self-administered opiate. Possible negative reinforcement from restoration of normal dopamine function remains speculative. This potential mechanism is, however, consistent with the view that continued opiate intake is necessary for normal psychological functioning independent of the positive reinforcing action associated with euphoria and mood elevation.7
Only limited data are available suggesting sensitization to the reinforcing effects of drugs.10 Pre-exposure to drug does seem to enhance the initial reinforcing impact of drug (e.g., Lett, 1989; Piazza, Deminière, Le Moal, & Simon, 1990). This is consistent with the proposed sensitization of a positive reinforcement mechanism, although other interpretations are equally viable. If opiates become increasingly effective in activating the ventral tegmental dopamine system with repeated use—and considerable data suggests that this system shows sensitization with both opiates and psychomotor stimulants—then the positive reinforcing impact of opiates would increase with chronic drug usage. This reward sensitization effect, along with a concomitant decrease in the ability of natural reinforcers to activate this system (i.e., devaluation of other motivational stimuli), would produce a particularly potent motivational effect.
Enhanced positive reinforcement from drug sensitization involves only a quantitative change in motivation but a qualitatively different mechanism physiologically.11 For this reason it might be considered an additional mechanism in the development of opiate addiction—one dependent on a neuroadaptive effect developing from repeated drug administration. But the basic motivational process remains positive reinforcement.
The motivational processes dependent on a ventral tegmental action are (i) positive reinforcement, (ii) enhanced positive reinforcement with a positive contrast effect, and (iii) negative reinforcement produced by normalization of depressed ventral tegmental dopamine function with the added feature of devalued competing reinforcers. The periventricular gray action involves a single negative reinforcement process related to the ability of opiates to relieve withdrawal distress. Hence, two negative reinforcement processes are involved—normalization of ventral tegmental dopamine function and relief of periventricular gray mediated withdrawal distress; two interdependent but temporally dissociable positive reinforcement processes are involved—activation of the physiologically normal ventral tegmental dopamine system and increased activation following sensitization to the drug action. This latter effect provides a mechanism for the enhanced motivational effect of opiates following chronic drug administration but still involving a positive reinforcement process.
The initial positive reinforcing impact of opiates involves an action shared with the psychomotor stimulants—activation of the ventral tegmental dopamine system. Continued drug intake probably produces neuroadaptive changes for both classes of drugs. Another action shared by these compounds may be depressed activity of this brain reward system when drug is absent and the subsequent negative reinforcement from continued drug intake. A mechanism not shared by these compounds involves the physical dependence syndrome produced by chronic opiate intake. The negative reinforcement obtained by the relief of opiate withdrawal discomfort may be unique to drugs that produce a clear physical dependence syndrome involving somatic disturbances.
The table summarizes four basic reinforcement mechanisms that may be operative during long-term opiate administration. Each of these mechanisms could contribute independently to drug-taking behavior, and some can be studied without the confounding influence of the other mechanisms. For example, positive reinforcement can be studied by limiting opiate action to the ventral tegmental area. And at least one negative reinforcement mechanism can be studied by restricting opiate action to the periventricular gray system. It is more difficult to dissociate the acute reinforcing and neuroadaptive effects within the ventral tegmental system. One approach might use low-dose, intermittent exposure to opiate in an attempt to minimize the development of neuroadaptive effects. Another approach would identify the molecular mechanisms mediating neuroadaptive responses and pharmacologically block these effects during chronic drug exposure. Such approaches to studying opiate reinforcement attempt to isolate individual reinforcement mechanisms to determine their separate contributions to drug-taking behavior.
Reassembling these multiple mechanisms is obviously important for considering the net reinforcing impact of opiates—these independent actions may combine in an additive fashion to produce the strong motivational impact characteristic of an addiction. What may not be so obvious is that other, derived processes may emerge from these primary motivational effects. Enhanced drug activation of this positive reinforcement substrate (i.e., sensitization of this reinforcement substrate to pharmacological activation) in a background of devalued conventional reinforcement (i.e., impaired ability of natural reinforcers to activate this system following physiologically depressed activity of this reinforcement substrate) may produce motivational toxicity and a type of motivational focusing unique to drug reinforcement. This characteristic may be the most salient feature of drug addiction and may involve an interactive effect of multiple reinforcement mechanisms. Without studying this and other derived processes, only mechanisms mediating the early stage of addiction can be addressed. A complete understanding of addiction thus necessitates reassembling multiple mechanisms to consider their interactive effects.
2. In the author's research, this has been accomplished in two ways—by using central opiate administration that limits drug action to relatively discrete brain regions and by studying short-term, low-dose opiate reward that presumably minimizes the development of neuroadaptive changes.
3. Withdrawal discomfort following abrupt termination of physical dependence-producing opiate injections may contribute to drug-taking behavior. Several brain regions are undoubtedly involved in physical dependence (e.g., Bozarth, 1994, Wei, Loh, & Way, 1973), but for simplicity only the periventricular gray region is considered here.
4. Technically, reinforcement always follows the behavior it reinforces. Presentation of a positive reinforcer clearly follows the behavior it reinforcers, while presentation of a negatively reinforcing stimulus precedes the behavior it reinforcers. But in the latter case, the reinforcing event is considered the removable of the motivating stimulus. With this interpretation, reinforcement follows the behavior it strengthens regardless of whether the reinforcing stimulus is functioning as a positive or negative reinforcer. Rather than become overly involved with the semantics of operant conditioning theory, it is far simpler to consider the negative reinforcer as the motivating stimulus that precedes the reinforced behavior even though the reinforcing event is termination of that stimulus.
5. One might argue that extrinsic motivators mediate initial drug-taking behavior. Indeed, some factor such as peer pressure or curiosity is necessary to explain the first occurrence of drug self-administration. But these extrinsic factors are totally inadequate explanations of the potent motivation characteristic of even the acquisition phase of drug addiction as drug use escalates with increasing cost to the individual.
6. Blocking opiate action in the ventral tegmentum increases intravenous heroin self-administration; this effect has been interpreted as decreasing the effectiveness of intravenously delivered heroin (viz., the effect parallels the effect of decreasing the heroin dose delivered with each intravenous infusion). Although this does indeed suggest that opiate action in the ventral tegmentum is important for the rewarding impact of systemically delivered drug, it is important to note that central narcotic antagonist injections fail to totally block opiate self-administration. These studies have been performed in subjects trained to self-administer opiate and these data suggest that other mechanisms are involved in the regulation of opiate intake during chronic administration.
7. This is the often cited rationale of methadone and heroin maintenance programs—continued opiate intake is necessary to maintain normal psychological functioning, even when overt signs of opiate use are absent.
8. Positive contrast effects are produced by an abrupt increase in the magnitude of a positive reinforcer (e.g., increasing the number of food pellets obtained by performing the operant response). Behavioral contrast effects are usually short lived; with repeated trials, the performance level adjusts to the new incentive value of the reinforcer. The mechanism proposed here requires maintenance of this behavioral contrast effect despite continued exposure to the reinforcer. One mechanism might involve continued sensitization to reward with repeated drug administration (see Lett, 1989).
9. Robinson and Berridge (1993) have recently suggested a theory of addiction focusing on sensitization of this dopamine system. Lett (1989) has also proposed sensitization as a major determinant of drug addiction.
10. Stress also activates the ventral tegmental dopamine system, and enhanced drug reinforcement following stress could involve cross sensitization of a positive reinforcement mechanism (see Piazza et al., 1990).
11. Different CNS sites may be involved in sensitization and activation of the ventral tegmental dopamine system (see Kalivas & Stewart, 1991). For example, amphetamine sensitization develops from an action in the cell-body region (i.e., ventral tegmentum), while the dopamine-enhancing effect results from an action in the synaptic terminal field (i.e., nucleus accumbens). Also, some neurochemical events necessary for sensitization are probably not involved in the primary pharmacological actions of these drugs; it may be possible to block sensitization by neurochemical manipulations that do not affect the primary positive reinforcement mechanism. An indirect test of this hypothesis comes from the recent demonstration that blocking a neurochemical system involved in cocaine sensitization (Pudiak & Bozarth, 1993) does not affect cocaine's facilitation of brain stimulation reward (Bozarth, Pudiak, & Morris, 1994).
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