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Relapse to drug-seeking: neural and molecular mechanisms
David W. Self* and Eric J. Nestler Division of Molecular Psychiatry, Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA Available online 18 June 1999 Article Outline
1. IntroductionOver the past several decades, there have been tremendous advances in our understanding of the neurobiology of drug addiction. Much of this work has focused on the neurobiological mechanisms of drug reward, which is viewed as a central factor in drug abuse (Koob and Bloom, 1988; Wise, 1990; Fibiger et al., 1992; Self and Nestler, 1995). Only more recently have studies focused on the neurobiological mechanisms of relapse, which is perhaps the core motivational symptom of compulsive drug taking and intense drug craving. A better understanding of the mechanisms of relapse could lead to more effective treatment strategies for addictive disorders. It is generally believed that the same neural systems involved in drug reward and drug-associated learning are also involved in relapse, since these phenomena can both elicit similar ‘drug-seeking' behavior. However, there are basically two theories that have diametrically opposite views on the role of brain reward pathways in mediating relapse to drug-seeking. One theory suggests that relapse is triggered by drug-like, or proponent, processes that activate reward pathways in a manner directionally similar to the acute effects of the drug themselves (Stewart et al., 1984; Wise and Bozarth, 1987; Robinson and Berridge, 1993; Self and Nestler, 1995). Another theory suggests that drug-opposite, or opponent, processes induce relapse by producing a hypofunctional state of reward pathways which leads to dysphoria or anxiety during withdrawal (Solomon and Corbitt, 1974; Koob and Le Moal, 1997). In this case, drug-seeking behavior represents an attempt to alleviate discomfort. Given that drug-seeking and drug craving can persist despite long periods of abstinence, both theories postulate that relatively long-term drug-induced neuroadaptations in brain reward and other regions underlie proponent and opponent processes (Fig. 1). A major gap in our current knowledge is identifying stable neuroadaptations that underlie these phenomena. Fig. 1. Both learning and pharmacological factors contribute to neuroadaptations to chronic drug use. These neuroadaptations can be manifested as either opponent (drug-opposite) or proponent (drug-like) processes. One major mechanism for producing such neuroadaptations is through the direct pharmacological effects of repeated drug exposure on brain cells. This type of neuroadaptation is exemplified by the classic studies of Nirenberg and colleagues on opiate tolerance and dependence (e.g. Sharma et al., 1975). In these studies, chronic exposure to morphine was found to up-regulate the cyclic AMP (cAMP) pathway in cultured cells as a result of homeostatic processes. Similar neuroadaptations have more recently been demonstrated in specific brain neurons (Nestler and Aghajanian, 1997). These neuroadaptations result in tolerance to the physiological effects of the opiate at the level of individual cells, and opposite physiological changes when the opiate is withdrawn. In a motivational sense, similar drug-induced neuroadaptations could also underlie tolerance to the rewarding effect of drugs and produce aversive consequences during drug withdrawal, thereby representing opponent processes. Conversely, the direct pharmacological effects of repeated drug exposure can produce proponent processes such as sensitization of cellular responses to the neurotransmitters dopamine and glutamate (Henry and White, 1991; White et al., 1995), which can increase sensitivity to the rewarding effects of drugs (Carlezon et al., 1997). A second major mechanism of neuroadaptation produced by repeated drug exposure underlies the powerful learned associations that are formed between the rewarding effects of drugs and specific environmental stimuli related to the drug-taking experience. These otherwise neutral environmental stimuli acquire the ability to trigger both drug- and withdrawal-like responses in addicted subjects when subsequently presented in the absence of the drug (Wikler, 1973; Siegel, 1983; O'Brien et al., 1992). While such ‘conditioned stimuli' or ‘cues' can trigger either mild euphoria or severe dysphoria, in both cases, the addicted subjects report an intense desire to self-administer their drug of choice. Similar proponent and opponent conditioned effects have been reported in animals (Wikler, 1973; Eikelboom and Stewart, 1982; Siegel, 1983; Robinson and Berridge, 1993). Although the direct (unconditioned) pharmacological influence of chronic drug exposure can produce neuroadaptations independent of drug-associated learning (e.g. Self et al., 1995), the conditioned effects of drugs can alter the manifestation of these processes (Wikler, 1973; Eikelboom and Stewart, 1982; Siegel, 1983; Robinson and Berridge, 1993), such that both conditioned and unconditioned factors ultimately contribute to the magnitude and expression of drug-associated neuroadaptations (Fig. 1). Ultimately, our understanding of drug addiction will require the elucidation of how the unconditioned and conditioned effects of drug exposure, as well as opponent and proponent processes, interact to induce relapse to drug-seeking. However, before the contribution of these complex interactions can be fully understood, it is important first to identify the neural systems that mediate relapse to drug-seeking. Drug craving and drug-seeking are subjective descriptions that cannot be directly measured in laboratory animals. However, relapse is an operant event that can be measured directly when a laboratory animal reinitiates a particular behavioral response, such as a lever-press that delivered drug injections on previous occasions during drug self-administration. Relapse to a prior behavioral response, often referred to as reinstatement, is thought to reflect the induction of drug-seeking following extinction from drug self-administration, when the animal's responses are no longer reinforced by the drug injections. The ability of specific experimenter-delivered stimuli to induce an animal to initiate responding at a ‘drug-paired' lever is then measured. Stimuli that effectively induce such responding are sometimes called ‘primers' because they are thought to initiate a renewed interest in drug-seeking. Although there are other animal models of drug craving and drug-seeking (e.g. Markou et al., 1993; Robinson and Berridge, 1993), the reinstatement paradigm dissociates measures of relapse from other behavioral phenomena, such as reward, extinction, and conditioned reward, that may or may not reflect similar neurobiological processes. It is important to emphasize, however, that relapse to responding associated with drug self-administration is the behavior measured in the laboratory; subjective descriptions like drug-seeking can only be inferred from this behavior. 2. Drug-induced relapse to drug-seeking behaviorA powerful trigger of relapse in the reinstatement paradigm is an experimenter-delivered priming injection of the self-administered drug after extinction from drug self-administration. This has been demonstrated for opiates and psychostimulants (Gerber and Stretch, 1975; de Wit and Stewart, 1981 and de Wit and Stewart, 1983; Slikker et al., 1984), but these drugs fail to reinstate responding in animals trained to self-administer barbiturates (Slikker et al., 1984). Conversely, barbiturates, benzodiazepines and ethanol all fail to reinstate responding for psychostimulants (Gerber and Stretch, 1975; de Wit and Stewart, 1981; Slikker et al., 1984; Comer et al., 1993). Since the ability of various drugs to induce relapse coincides with their ability to mimic the subjective effects of the self-administered drug, investigators originally concluded that the subjective effects of a particular drug are a primary determinant of whether the drug could induce relapse to drug-seeking behavior. However, recent studies suggest that it is neither necessary (Shaham and Stewart, 1995a and Shaham and Stewart, 1995b) nor sufficient (Self et al., 1996a) for priming stimuli that induce relapse to also have subjective effects similar to those produced by the self-administered drug. Moreover, a recent study has found that the incentive motivational properties of morphine occur in the absence of detectable subjective effects in animals measured by drug discrimination, further suggesting separate neural substrates for motivational and subjective drug effects (Jaeger and van der Kooy, 1996). Interestingly, opiates can reinstate responding in animals trained to self-administer psychostimulants (de Wit and Stewart, 1981; Slikker et al., 1984), and vice versa (de Wit and Stewart, 1983). This ‘cross-priming' could reflect activation of a common neural substrate by the two drug classes. Indeed, both opiates and psychostimulants can produce rewarding effects by activating the mesolimbic dopamine system (Wise and Bozarth, 1987; Di Chiara and Imperato, 1988), consisting of dopaminergic neurons in the ventral tegmental area (VTA) and their target neurons in the nucleus accumbens (NAc). Considerable evidence suggests that the ability of opiates and psychostimulants to trigger relapse to drug-seeking behavior also involves their ability to activate the mesolimbic dopamine system. Microinfusion of amphetamine directly into the NAc, where it causes local dopamine release, effectively reinstates heroin-seeking behavior (Stewart and Vezina, 1988). Similarly, application of morphine directly into the VTA, where it activates dopamine neurons via disinhibition (Johnson and North, 1992), and consequently increases dopamine release in the NAc (Leone et al., 1991), can reinstate both heroin- and cocaine-seeking behavior (Stewart et al., 1984). Injections of morphine into other brain regions rich in opiate receptors, including the NAc, are ineffective at inducing relapse to drug-seeking behavior. Further evidence for dopamine involvement in drug-induced relapse is the fact that several directly acting dopaminergic agonists are powerful inducers of relapse to both cocaine- and heroin-seeking behavior (de Wit and Stewart, 1983; Wise et al., 1990; Self et al., 1996b), and dopamine antagonists can block the priming effects of heroin, amphetamine and cocaine (Ettenberg, 1990; Shaham and Stewart, 1996; Weissenborn et al., 1996). Taken together, these studies suggest that drug-induced dopamine release in the NAc is both necessary and sufficient for opiate and psychostimulant drugs to induce relapse to drug-seeking behavior (Fig. 2). Fig. 2. Diagrammatic representation of the primary pathways through which stress, drugs of abuse, and drug-associated stimuli are hypothesized to trigger relapse to drug-seeking behavior. Stress and drug-associated stimuli can activate excitatory glutamate (Glu) projections to the ventral tegmental area (VTA) from the prefrontal cortex (PfC) and amygdala (Amyg), respectively, while drugs of abuse stimulate dopamine (DA) release from VTA dopamine neurons projecting to the nucleus accumbens (NAc). Amyg projections to the PfC represent a secondary pathway through which drug-associated stimuli could access VTA dopamine neurons. Similarly, stress-induced relapse may utilize corticotropin releasing factor (CRF) and the hypothalamo–pituitary–adrenal (HPA) axis, and subsequent corticosterone (Cort) secretion to activate VTA dopamine neurons. Although dopamine release in the NAc may be a final common neurochemical event that triggers relapse by all three stimuli, stress and CRF may also act on other unknown brain regions through dopamine-independent mechanisms to trigger relapse to drug-seeking behavior. 3. Cue-induced relapse to drug-seeking behaviorA second trigger of relapse in the reinstatement paradigm is the presentation of drug-associated stimuli or cues. In animals, reports of cue-induced relapse to drug-seeking behavior are sparse (de Wit and Stewart, 1981; Meil and See, 1997), but reports of cue-induced drug craving in humans are numerous (see Introduction). Moreover, the priming induced by drug-associated stimuli in animals is relatively weak when compared to the priming induced by the self-administered drug (de Wit and Stewart, 1981). Nevertheless, the fact that these drug-associated stimuli can trigger drug-seeking behavior has led investigators to hypothesize that these stimuli activate the mesolimbic dopamine system (Stewart et al., 1984; Robinson and Berridge, 1993; Wise, 1994). At present, this hypothesis remains equivocal, because some studies have found that the conditioned behavioral effects of cocaine are not necessarily associated with an increase in dopamine release in the NAc (Brown and Fibiger, 1992). However, at least two studies have reported enhanced dopamine release in the NAc following presentation of drug-associated cues (Fontana et al., 1993; Di Ciano et al., 1995). In addition, others have found that dopamine neurons in the VTA are activated by environmental stimuli associated with non-drug rewards, and these cues also elicit reward-seeking behavior (Schultz et al., 1993; Mirenowicz and Schultz, 1996). Although elusive, the question of dopamine involvement in conditioned drug effects is crucial to our understanding of how drug-associated cues access motivational systems to trigger relapse. Already established is a role for the amygdala in the priming effects of drug-associated cues. Meil and See (1997) recently reported that excitatory amino acid lesions of the basolateral nucleus of the amygdala attenuate the ability of cocaine-associated cues to induce relapse to cocaine-seeking behavior. These lesions effectively block cue-induced relapse even when the amygdala is lesioned after cue conditioning already had occurred, indicating that the amygdala is part of an important neural pathway through which cocaine-associated cues access and activate incentive motivational systems. Similar lesions of the amygdala were found to block the conditioned motivational, but not the conditioned locomotor, effects of cocaine (Brown and Fibiger, 1993), suggesting separate neural substrates for each of these conditioned effects. The descending outputs of the amygdala are thought to be excited by sensory information from conditioned stimuli (LeDoux, 1993). One of the descending outputs is an excitatory amino acid projection from the central nucleus to VTA dopamine neurons (see Fig. 2) (Gonzales and Chesselet, 1990; Wallace et al., 1992), and stimulation of this pathway can excite VTA dopamine neurons through both mono- and poly-synaptic pathways (Maeda and Mogenson, 1981), presumably leading to increased dopamine levels in the NAc. Fig. 2 illustrates this direct pathway whereby drug-associated stimuli could activate the mesolimbic dopamine system via excitatory inputs, leading to dopamine release in the NAc and relapse to drug-seeking. However, amygdala projections to other brain regions such as the prefrontal cortex (PfC) could form secondary pathways through which drug-associated stimuli activate VTA dopamine neurons (McDonald, 1991). Amygdala projections to terminal regions in the NAc apparently make synaptic contacts with NAc perikarya rather than dopamine terminals (Johnson et al., 1994), and thus are not be expected to directly stimulate dopamine release. 4. Stress-induced relapse to drug-seeking behaviorPreviously, Shaham and Stewart (Shaham and Stewart, 1995a; Shaham et al., 1996) reported that a brief presentation of intermittent footshock stress induces a robust and prolonged reinstatement of heroin-seeking behavior in rats with prior heroin self-administration experience. This stressor effectively induced heroin-seeking behavior in both opiate-dependent and non-dependent animals, and was capable of inducing relapse even after 6 weeks of withdrawal from heroin. A similar priming effect of footshock stress on cocaine-seeking behavior has since been demonstrated following prolonged extinction from cocaine self-administration (Erb et al., 1996; Ahmed and Koob, 1997). In some cases, the ability of stress to induce drug-seeking behavior in animals was greater than priming injections of the drug itself. As with drugs and conditioned stimuli, stress-induced relapse to drug-seeking behavior also may involve activation of dopamine receptors in the NAc. This notion is supported by the finding that stress-induced elevations in NAc dopamine levels correlate temporally with reinstatement of heroin-seeking behavior (Shaham and Stewart, 1995b). Moreover, stress-induced relapse to this behavior can be partially attenuated by pretreatment with dopamine antagonists (Shaham and Stewart, 1996). The primary neural pathway through which stress can stimulate dopamine release in the NAc may involve stress effects on the PfC (Moghaddam, 1993) and, consequently, activation of an excitatory projection from the PfC to the VTA (Fig. 2). This projection forms monosynaptic inputs to VTA dopaminergic neurons (Sesack and Pickel, 1992), and can trigger dopamine release in the NAc (Murase et al., 1993). Although the PfC also sends excitatory projections to the NAc (Sesack et al., 1989; Brog et al., 1993), recent studies have found that PfC regulation of NAc dopamine levels is mediated primarily via activation of glutamate receptors on VTA dopamine neurons, and not on dopamine terminals in the NAc (Taber et al., 1995; Karreman and Moghaddam, 1996). Fig. 2 shows that stress could also activate or enhance mesolimbic dopamine transmission through release of corticotropin releasing factor (CRF). Shaham and colleagues have recently found that intracerebroventricular (ICV) infusions of CRF mimicked the induction of heroin-seeking behavior triggered by stress, and similar infusions of a peptide CRF antagonist partially reduced stress-induced relapse (Shaham et al., 1997). ICV CRF administration has been reported to increase dopamine release in the hypothalamus and prefrontal cortex (Lavicky and Dunn, 1993; Song et al., 1995), although CRF effects on dopamine release in the NAc have not been reported. In addition, CRF could also potentiate activity in VTA dopamine neurons through its effect on the hypothalamo–pituitary–adrenal (HPA) axis, because systemic corticosterone injections increase the sensitivity of VTA dopamine neurons to excitatory inputs, and lead to greater dopamine release in the NAc (Overton et al., 1996; Piazza et al., 1996). However, while stress-induced relapse to cocaine-seeking behavior could rely on the HPA axis and corticosterone secretion (Piazza et al., 1994; Deroche et al., 1997), stress-induced relapse of heroin-seeking behavior can apparently occur independently of corticosterone secretion (Shaham et al., 1997). Together, these studies suggest that stress can activate VTA dopamine neurons through activation of the PfC, and through CRF–HPA–corticosterone feedback on the VTA-NAc pathway (Fig. 2). However, stress was found to be less effective than priming injections of heroin at stimulating dopamine release in the NAc, despite greater induction of heroin-seeking behavior by the stressor (Shaham et al., 1996). This may suggest that stress-induced relapse likely involves dopamine-independent mechanisms as well (Fig. 2). 5. Opponent vs. proponent processes as triggers of relapseIt is clear from these studies that proponent processes are powerful inducers of relapse in animal models of drug-seeking behavior because, without exception, stimuli that induce relapse are also capable of releasing dopamine in the NAc. In contrast, several studies have found that opponent processes fail to induce relapse in these animal models. For example, priming injections of opiate antagonists fail to induce relapse and actually suppress drug-seeking behavior in non-opiate-dependent animals (Stewart and Wise, 1992). Even in opiate-dependent animals, antagonist-precipitated withdrawal fails to induce heroin-seeking behavior, despite withdrawal-induced decreases in dopamine levels in the NAc (Shaham et al., 1996). Similarly, dopamine receptor antagonists fail to induce heroin- or cocaine-seeking behavior (Shaham and Stewart, 1996; Weissenborn et al., 1996). The inability of these antagonist treatments to induce relapse contrasts sharply with their ability to produce aversive consequences (Shippenberg and Herz, 1987; Stinus et al., 1990), suggesting that opponent motivational processes do not trigger relapse. Thus, animal studies agree with reports of drug-like, and even mood elevating, symptoms of craving in cocaine addicts (Childress et al., 1988). However, these animal studies are in contrast with human reports of drug-craving associated with drug-opposite symptoms such as dysphoria, especially in opiate addicts and alcoholics (Childress et al., 1988). Although antagonist-precipitated withdrawal fails to trigger relapse to drug-seeking behavior in animals, spontaneous withdrawal in opiate-dependent animals does induce relapse to heroin-seeking behavior without any detectable change in NAc dopamine levels (Shaham et al., 1996). This finding may be relevant to other factors involved in maintaining daily drug use in active drug abusers. In this sense, falling levels of opiate during spontaneous withdrawal is an example of an opponent process that could trigger drug craving and relapse on a day-to-day basis, while proponent processes may be more important in triggering relapse after longer periods of abstinence, when withdrawal symptoms have dissipated. Stress- and CRF-induced relapse apparently have characteristics of proponent processes, since both activate central dopamine release (Lavicky and Dunn, 1993; Song et al., 1995), and cocaine acutely elevates CRF levels in the amygdala (Sarnyai et al., 1993; Richter et al., 1995). However, withdrawal from cocaine (Sarnyai et al., 1995), opiates (Katsumata et al., 1995), ethanol (Pich et al., 1995), or cannabinoids (Rodriguez de Fonseca et al., 1997) is also associated with elevated CRF levels in the amygdala, and this effect is thought to mediate anxiogenic effects during drug withdrawal. A critical question is whether CRF-induced anxiety contributes to relapse to drug-seeking behavior and, if so, would this effect be independent of CRF effects on the mesolimbic dopamine system. 6. Receptor mechanisms of dopamine-induced relapseThe studies described in the preceding sections suggest that relapse to drug-seeking can be triggered by activation of post-synaptic dopamine receptors on NAc neurons. Dopamine receptors are divided into two general classes that are distinguishable by their structural properties and opposite modulation of adenylyl cyclase (Sibley et al., 1993). The D1-like receptors (D1 and D5) are positively coupled to adenylyl cyclase activity, while the D2-like receptors (D2, D3 and D4) are either negatively coupled or have no detectable effect on the enzyme. The two receptor classes also exert opposite effects on phosphatidylinositol turnover. Neurons intrinsic to the NAc express both D1-like and D2-like dopamine receptors, but in somewhat different neuronal populations (Meador-Woodruff et al., 1991; Curran and Watson, 1995 and Gerfen and Wilson, 1996). In most cases, these receptors produce similar, even synergistic, responses at the physiological and behavioral levels (Waddington and Daly, 1993; White and Hu, 1993). In contrast to these cooperative actions, we found that systemic priming injections of D2-like, but not D1-like, dopamine receptor agonists induce a profound and prolonged relapse to cocaine-seeking behavior in rats in the reinstatement paradigm (Self et al., 1996a). These findings suggest that D2-like receptors are primarily involved in inducing drug-seeking behavior by priming stimuli that release dopamine in the NAc. Although selective D1-like receptor agonists fail to markedly induce cocaine-seeking behavior, D1 receptors may have a permissive role in the priming effects mediated by D2 receptors, since both D1- and D2 receptor antagonists can block the priming effects of cocaine and heroin (Shaham and Stewart, 1996; Weissenborn et al., 1996). Further support for this idea is the finding that relatively high doses of D1 antagonists are required to attenuate the priming effects of cocaine and heroin compared to other drug-related behaviors. Thus, transmission of D2-mediated priming signals may require some minimal level of D1 receptor activation. Interestingly, however, pretreatment with D1-like agonists completely abolishes the ability of priming injections of cocaine to induce relapse, whereas pretreatment with D2-like agonists, at doses too low to induce relapse on their own, greatly potentiates priming with cocaine. The opposing influence of D1-like and D2-like dopamine receptor activation on relapse to cocaine-seeking behavior is intriguing since both D1 and D2 receptor agonists have reinforcing properties (e.g. Self and Stein, 1992; Caine and Koob, 1993), have similar abilities to mimic the subjective effects of cocaine (Callahan et al., 1991; Spealman et al., 1991; Witkin et al., 1991), and stimulate locomotor activity (Self et al., 1996b). One possible explanation for these findings is that D2-like receptors mediate the incentive to seek further drug reinforcement, while D1-like receptors could mediate some aspect of drug reward related to gratification, drive reduction, or satiety. The psychostimulant caffeine also can induce relapse to cocaine-seeking behavior, as well as enhance the priming effects of cocaine (Worley et al., 1994; Self et al., 1996a). Caffeine's psychostimulant effects are mediated by an antagonist action at striatal A2 adenosine receptors, which are positively coupled to adenylyl cyclase. Moreover, a specific post-synaptic interaction between A2 and D2 receptors has been found, where blockade of A2 adenosine receptors by caffeine enhances the affinity of D2 receptors for dopamine (Ferre et al., 1992). This post-synaptic interaction could underlie relapse to cocaine-seeking behavior induced by caffeine by potentiating D2-mediated priming signals. Although many of the behavioral and physiological responses of D1-like and D2-like receptors in the NAc are similar (Waddington and Daly, 1993; White and Hu, 1993), the two receptor types have opposite effects on adenylyl cyclase and phosphatidylinositol turnover (see above), which could possibly underlie their opposing effects on relapse to drug-seeking behavior. In view of this, we recently found that experimental modulation of the cAMP pathway in the NAc has a profound effect on relapse to cocaine-seeking behavior in rats with cocaine self-administration experience (Self et al., 1998). In this study, membrane-permeable cAMP analogs, Rp- and Sp-cAMPS, were infused bilaterally into the NAc of rats in a reinstatement paradigm (Fig. 3). Rp-cAMPS inhibits the cAMP pathway by preventing endogenous cAMP from activating cAMP-dependent protein kinase (PKA). Infusion of the PKA inhibitor into the NAc triggers relapse to cocaine-seeking behavior, and pretreatment with a subthreshold dose of the kinase inhibitor enhances the priming effects of intravenous cocaine injections. Thus, NAc infusion of the PKA inhibitor mimicked the effects of systemic priming injections of D2-like agonists. This supports the hypothesis that D2-like receptors may utilize inhibition of PKA activity, at least in part, to induce relapse to drug-seeking behavior. In any event, this finding suggests that PKA activity in certain NAc neurons could play a pivotal role in regulating incentive motivation during drug craving and relapse. Fig. 3. Effects of intra-NAc infusions of the PKA inhibitor Rp-cAMPS or the PKA activator Sp-cAMPS (both at 40 nmol/1 μl/side) on the priming effects of intravenous cocaine injections (2.0 mg/kg) in the reinstatement paradigm. These treatments were given after extinction from 2 h of intravenous cocaine self-administration, when only intravenous saline injections were available. Hatch marks denote the times of each self-infusion of cocaine in the cocaine phase and saline in the saline phase (from Self et al., 1998). In contrast, intra-NAc infusion of the PKA activator, Sp-cAMPS, masks or disrupts the priming effects of cocaine, but also induces generalized behavioral responses that cannot be attributed to relapse of drug-seeking behavior (Self et al., 1998). The fact that D1-like agonists, which also stimulate PKA activity, fail to mimic these latter effects may suggest that: (i) the behavioral effects of Sp-cAMPS result from effects on NAc neurons that do not contain D1-like receptors; (ii) D1-like receptor responses in the NAc utilize additional signal transduction pathways; or (iii) D1-like receptors involved in suppressing drug-seeking are located outside the NAc. Studies are currently underway to test whether alternative signalling pathways and brain sites are utilized by D1 receptors to attenuate relapse to cocaine-seeking behavior. 7. Possible role of drug-induced neuroadaptations in the NAc cAMP second messenger system in relapsePrevious work has identified neuroadaptations in the NAc cAMP pathway after chronic exposure to opiates, cocaine, or ethanol as shown in Fig. 4 (see Self and Nestler, 1995; Nestler and Aghajanian, 1997). These neuroadaptations are characterized by decreased levels of inhibitory G proteins that inhibit cAMP formation, and by increased levels of adenylyl cyclase and PKA activity, that can persist for several weeks into withdrawal (Striplin and Kalivas, 1993; Self and Nestler, 1995; Schoffelmeer et al., 1996; Unterwald et al., 1996). Decreases in the level of inhibitory G proteins, coupled with increases in the biochemical machinery to synthesize and respond to cAMP, all contribute to a generalized up-regulation of the NAc cAMP pathway. These neuroadaptations probably result from the direct pharmacological effect of repeated drug exposure rather than from drug-associated learning, since they occur to a similar extent whether animals learn to self-administer drugs, or if they receive the same amount and pattern of drug administration by passive infusions (Self et al., 1995). Fig. 4. Similarities in post-receptor neuroadaptations in the NAc produced by chronic exposure to opiates, cocaine, or ethanol. Chronic drug exposure decreased levels of inhibitory G proteins (Gi and Go), and increased adenylyl cyclase (AC) and of particulate and soluble cAMP-dependent protein kinase (PKA) activity in NAc extracts. See Self and Nestler (1995) and Nestler and Aghajanian (1997) for references to original data. Asterisks indicate that values differ from saline-treated controls by χ2-test (*P<0.05). In our recent report (Self et al., 1998), we tested the effects of experimentally up-regulating the cAMP pathway in the NAc on cocaine self-administration by infusing the PKA activator, Sp-cAMPS, into the NAc. Fig. 5 (upper panel) shows that experimental activation of the PKA pathway in the NAc produces increases in cocaine self-administration, resulting in a rightward shift in the cocaine self-administration dose response curve. Since a similar effect is produced by pretreating animals with dopamine antagonists (e.g. Caine and Koob, 1994), this effect is usually interpreted as a reduction in cocaine reward, and animals compensate by increasing their drug intake. Similar increases in cocaine and heroin self-administration are seen after inactivation of NAc inhibitory G proteins with pertussis toxin (Self et al., 1994). Thus, artificially mimicking the drug-induced neuroadaptations in the NAc by sustained down-regulation of inhibitory G proteins or by sustained increases in PKA activity both produce increases in drug-self-administration. Taken together, these findings suggest that drug-induced neuroadaptations in the NAc cAMP pathway represent an intracellular mechanism of tolerance to the rewarding properties of drugs and, hence, would constitute an opponent process type of neuroadaptation. Possible mechanisms for PKA-induced tolerance to the rewarding effects of cocaine could involve D1 receptor phosphorylation and desensitization caused by sustained PKA activity (Sibley et al., 1998). Fig. 5. Effects of PKA activation in the NAc with bilateral infusions of Sp-cAMPS (upper panel), and PKA inhibition with Rp-cAMPS (lower panel) on the dose–response relationship for cocaine self-administration. Self-administration rates are shown for the 2nd hour in experiments with the PKA activator, and during the 1st hour of the test session in experiments with the PKA inhibitor, when the cAMP analogs produced their maximal behavioral effects. Sustained activation of PKA produces an antagonist-like attenuation of cocaine effects in self-administration, while inhibition of PKA activity acutely enhances cocaine effects. The cAMP analogs were infused at doses of 40 and 80 nmol/1.0 μl/side). Data are from Self et al. (1998). Asterisks indicate that values differ from baseline values by paired t-test for the 40 or 80 nmol/side dose (*P<0.05; **P<0.01; ***P=0.001). Conversely, experimental inhibition of NAc-PKA activity by infusing the PKA inhibitor, Rp-cAMPS, directly into the NAc produces leftward shifts in the cocaine self-administration dose–response curve, consistent with an enhancement of cocaine effects (Fig. 5, lower panel). As with the relapse paradigm, the effect of the PKA inhibitor on cocaine self-administration resembles the effect of pretreatment with a D2-like dopamine receptor agonist (Caine and Koob, 1995). Taken together, these studies suggest that acute inhibition of PKA activity in the NAc is a proponent process that enhances cocaine reward, and triggers relapse to drug-seeking behavior similar to priming stimuli that release dopamine in the NAc. The hypothesis that drug-induced up-regulation of the NAc cAMP pathway increases the probability of relapse seems paradoxical, given that acutely it is inhibition, and not activation, of the pathway that triggers relapse. However, it is possible that tonic or sustained up-regulation of the NAc cAMP pathway could enhance the responsiveness of the system to stimuli that phasically inhibit it. This type of synergism is easily demonstrated in vitro, where prior activation of adenylyl cyclase dramatically augments the inhibitory signals produced by subsequent D2-like receptor activation (Battaglia et al., 1985). A similar synergy may occur in vivo, where tonic increases in the NAc-cAMP pathway caused by chronic drug exposure enhance the relative signal strength produced by phasic stimuli that inhibit cAMP activity during drug withdrawal (Fig. 6). If so, the priming ability of stimuli that release dopamine in the NAc, leading to D2-like receptor-mediated inhibition of PKA activity, would be markedly enhanced in addicted subjects. Although hypothetical, this idea suggests that tonic opponent and phasic proponent processes interact synergistically to augment the incentive produced by priming stimuli. Studies on conditioned reinforcement provide indirect support for this hypothesis by finding that the incentive properties of reward-associated stimuli, which are enhanced by acute stimulation of D2-like receptors (Beninger and Ranaldi, 1992), are also enhanced by tonic up-regulation of the NAc cAMP pathway (Kelley and Holahan, 1997). Thus, neuroadaptations in the NAc cAMP system could produce tolerance to the rewarding effects of drugs while simultaneously enhancing the incentive to seek them, effects commonly reported in human drug abusers.
8. Molecular basis of drug-induced neuroadaptationsThe precise molecular mechanisms by which chronic drug exposure leads to neuroadaptations in inhibitory G proteins, the cAMP pathway, and other target genes (e.g. receptors, transporters and neuropeptides, to name a few) is still unknown, but several studies have found that the long-term effects of repeated drug exposure involve changes in gene expression (for review see Self and Nestler, 1995; Hyman, 1996; Nestler and Aghajanian, 1997). Studies of the regulation of gene expression by drugs of abuse have focused on two families of transcription factors: cAMP Response Element Binding protein (CREB), and the products of certain immediate early genes (IEGs), such as c-fos and c-jun. Most genes likely contain numerous response elements for these and many other transcription factors, suggesting that complex interactions among multiple mechanisms control the expression of a given gene. Chronic exposure to morphine reduces CREB levels specifically in the NAc (Widnell et al., 1996). In contrast, acute and repeated administration of amphetamine increases CREB phosphorylation, without changing the level of CREB (Cole et al., 1995). This prolonged phosphorylation of CREB may be due to drug-induced up-regulation of the cAMP pathway, as described earlier. Involvement of CREB-regulated gene expression in drug-induced neuroadaptations is suggested by a recent study which found that disruption of the α and δ isoforms of CREB blocks development of analgesic tolerance and physical dependence to chronic opiate exposure (Maldonado et al., 1996). Preliminary work shows that changes in CREB function in the NAc alter the locomotor-activating and rewarding effects of cocaine (Self et al., 1996b; Lane et al., 1997). Along these lines it is possible that drug-induced changes in CREB's transcriptional activity lead to neuroadaptations that contribute to drug craving and relapse to drug-seeking. Moreover, a general role for CREB in long-term neuroplastic events is suggested by CREB's involvement in long-term potentiation and other cellular models of learning and memory [see Nestler and Aghajanian (1997) for references] suggesting that CREB could also mediate neuroadaptations that underlie drug-associated learning. Drug-induced neuroadaptations in the NAc may also involve changes in the transcriptional activity of IEGs. For example, certain Fos-like proteins or Fos-Related Antigens, termed chronic FRAs, are not induced by acute drug exposure, but are markedly induced in the NAc by chronic cocaine, morphine, amphetamine or nicotine exposure (Hope et al., 1994; Nye and Nestler, 1996; Pich et al., 1997). The chronic FRAs are known to be highly stable isoforms of ΔFosB (Chen et al., 1997). Moreover, mutant mice lacking the gene for ΔFosB show heightened sensitivity to cocaine's locomotor and rewarding effects (Hiroi et al., 1997). These initial studies indirectly suggest that ΔFosB-regulated gene transcription may be involved in long-lasting opponent process neuroadaptations to repeated drug exposure. A major challenge of future research is to further characterize drug-induced changes in CREB, ΔFosB, and other transcription factors in the NAc and other brain regions, and to identify the numerous target genes whose expression is altered by these transcription factors. Ultimately, it will be necessary to relate each of these neuroadaptations to specific behavioral responses to drugs of abuse, in particular to the propensity for relapse to drug-seeking behavior. 9. SummaryA central determinant of addictive
disorders in people is increased risk of relapse to drug use
even after prolonged periods of abstinence. Recent advances
in animal models of relapse indicate that drug-seeking
behavior can be triggered by priming injections of the drugs
themselves, by drug-associated environmental stimuli, and by
footshock stress. The neural mechanisms underlying this
relapse can be viewed in general terms as drug-like or
proponent processes. Considerable evidence points to the
mesolimbic dopamine system, and more specifically to
activation of D2-like dopamine receptors in the
nucleus accumbens, as a crucial neural substrate utilized by
various stimuli that induce relapse. Drug-associated stimuli
and stress may activate this system via neural circuits from
the prefrontal cortex and amygdala as well as via the
hypothalamo–pituitary–adrenal axis. There is also evidence
for dopamine-independent mechanisms in relapse as well. A
major effort of current research is to identify the
long-lasting neuroadaptations within these various brain
regions that contribute to relapse in addicted people. One
potential neuroadaptation is up-regulation of the cAMP
pathway in the nucleus accumbens, which occurs after chronic
drug exposure, and represents a drug-opposite or opponent
process. Modulation of this system has been related directly
to relapse to drug-seeking behavior. Given the long-lasting
nature of increased risk of relapse, it is likely that the
relevant neuroadaptations are mediated via drug-induced
changes in gene expression. A detailed understanding of the
neural and molecular basis of relapse will facilitate
efforts to develop truly effective treatments and preventive
measures. AcknowledgementsThis work was supported by grants from the National Institute on Drug Abuse, and by the Abraham Ribicoff Research facilities of the Connecticut Mental Health Center. We thank Przemyslaw Bienkowski and Christina Schad for their helpful comments on this manuscript ReferencesAhmed, S.H. and Koob, G.F., 1997. Cocaine- but not food-seeking behavior is reinstated by stress after prolonged extinction. Psychopharmacology 132, pp. 289–295 Full Text via CrossRef Battaglia, G., Norman, A.B., Hess, E.J. and Creese, I., 1985. D2 dopamine receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in rat. Neurosci. Lett. 59, pp. 177–182 Abstract | Abstract + References | PDF (320 K) Beninger, R.J. and Ranaldi, R., 1992. The effect of amphetamine, apomorphine, SKF 38393, quinpirole and bromocriptine on responding for conditioned reward in rats. Behav. 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