CARTCocaine and the Changing Brain Cocaine Dependence And Withdrawal: Neuroadaptive Changes In Brain Reward And Stress Systems
Friedbert Weiss, Ph.D.
The Scripps Research Institute
La Jolla, CAA growing body of evidence indicates that chronic cocaine administration can produce profound and long-lasting changes in brain neurochemical and neuroendocrine systems. At the behavioral level, evidence is accumulating that chronic use of cocaine compromises the neural mechanisms that mediate positive reinforcement. This is illustrated, for example, by findings that cocaine acutely facilitates the rewarding effects of intracranial self-stimulation, while withdrawal after chronic use leads to an impairment in the rewarding efficacy of electrical brain stimulation (Markou and Koob 1991). Findings such as these have given rise to the view that compulsive drug-seeking behavior associated with cocaine (and other drugs of abuse) may be the result of adaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs, leading both to a "blunting" of mechanisms that mediate positive reinforcement and the emergence of affective changes during withdrawal that may motivate continued use of the drug (for example, anxiety, dysphoria, and depression) during withdrawal (Koob and Bloom 1988; Koob et al. 1993; Wise 1996).
The following discussion reviews both earlier and recent studies that have sought to identify the brain neurochemical processes responsible for the compromised state of the reward system after chronic cocaine abuse and the significance of those processes in the transition from controlled drug use to compulsive drug-taking.
Neuroadaptive Changes Within Brain Reward CircuitriesIntravenous self-administration in rodents has been used successfully to study cocaine-reinforced behavior. This methodology has significantly advanced the understanding of the neurobiological basis of cocaine reinforcement and has established a critical role for the mesoaccumbens dopamine (DA) systems in cocaine's acute reinforcing effects. More recently, studies employing intracranial microdialysis measures of DA in the nucleus accumbens (NAc) of cocaine self-administering rats have confirmed the significance of DA in cocaine reward and extended our understanding of interactions among cocaine, DA, and other transmitters in this brain region in the regulation of cocaine-seeking behavior.
When given the opportunity, both human cocaine abusers and laboratory animals will often self-administer cocaine in sustained episodes that can last from several hours to days. In humans, in particular, this so-called binge pattern of cocaine abuse is associated with severe abstinence syndrome. In animals, termination of access to cocaine after long-term unrestricted intravenous self-administration produces behavioral disruptions and reward deficits believed to be indicative of dependence and withdrawal (Markou and Koob 1991). Therefore, this model was employed in conjunction with intracranial microdialysis to study the neurochemical consequences of long-term cocaine self-administration and cocaine withdrawal.
Dopamine.
Cocaine self-administration produced persistent elevations in extracellular DA concentrations in the NAc that remained stable throughout 12- to 24-hour periods of drug availability. Withdrawal from cocaine resulted in a marked suppression of DA release below basal levels prior to self-administration (Weiss et al. 1992b). Maximal inhibition of DA efflux was reached within 2 to 4 hours postcocaine, and the depression in extracellular DA levels did not recover within a 12-hour monitoring period. The degree of suppression of DA release was positively correlated with the number of hours of continuous cocaine self-administration before withdrawal. Interestingly, as shown in earlier work, deficits in brain stimulation reward also increased as a function of the duration of continuous self-administration prior to withdrawal and were reversible by administration of bromocriptine (Markou and Koob 1991, 1992; Weiss et al. 1995). These data implicate a link between the withdrawal-associated impairment in mesolimbic DA neurotransmission and behavioral abstinence symptoms as measured by attenuated brain stimulation reward. However, it is important to note that brain stimulation reward deficits are already evident shortly after termination of access to cocaine, at a time when there is still some residual elevation, rather than a deficit, in accumbal extracellular DA levels. This observation supports the hypothesis that sustained dopaminergic stimulation by long-term cocaine self-administration leads to adaptation of brain mechanisms that mediate positive reinforcement.
Serotonin.
Cocaine self-administration not only increases extracellular DA levels in the NAc but also produces similar elevations in extracellular serotonin (5-HT). Given the established role of 5-HT in depression, a prominent cocaine withdrawal symptom, it was of interest to determine whether cocaine withdrawal exerts disruptive effects on 5-HT neurotransmission.
Withdrawal after 12 hours of unrestricted access to cocaine produced a substantial suppression of 5-HT release in the NAc. Compared with basal 5-HT levels in cocaine-naive controls, 5-HT efflux as measured by quantitative microdialysis methods decreased by more than 50 percent as early as 6 hours postcocaine (Parsons et al. 1995). In contrast to the serotonergic deficits after long-term cocaine self-administration, only a trend toward suppression of basal 5-HT release was apparent in rats after 24 hours of abstinence from daily 3-hour limited-access self-administration. These findings are consistent with several reports in the literature of supersensitivity of 5-HT1a autoreceptors and increased density of 5-HT uptake sites after intermittent cocaine administration, but they also suggest that marked extracellular consequences of these presynaptic changes become evident only after prolonged periods of continuous cocaine self-administration. Decreased serotonergic transmission has been implicated in symptoms of numerous psychiatric disorders such as depression, panic disorder, insomnia, impulsiveness, and aggression-symptoms also associated with cocaine abstinence. Therefore, the deficit in extracellular 5-HT concentrations may contribute directly to many aspects of the cocaine withdrawal syndrome.
In addition to suppressing the release of 5-HT, withdrawal after long-term access to intravenous cocaine altered the sensitivity of 5-HT1b receptors. Locomotor activation in response to a 5-HT1b agonist (RU 24969) was diminished during the first 2 days of cocaine withdrawal, while a persistent rebound supersensitivity to 5-HT1b receptor activation emerged 1 week after cocaine withdrawal. The initial subsensitivity is likely to reflect an adaptive "downregulation" of 5-HT1b receptors that develops during long-term cocaine self-administration to compensate for the sustained cocaine-induced increases in synaptic 5-HT levels. Conversely, the subsequent supersensitivity is presumably the result of sustained extracellular 5-HT deficiency during cocaine withdrawal. These findings implicate 5-HT1b receptors, both in the cocaine withdrawal syndrome and in locomotor sensitization produced by repeated cocaine administration.
Recent studies have implicated the 5-HT1b receptor in the acute reinforcing actions of cocaine. The 5-HT1b agonists produced a dose-dependent shift to the left in the dose-effect function for self-administered cocaine and elevated breaking points for cocaine on a progressive ratio schedule (Parsons et al., submitted). The enhancement of cocaine reward by 5-HT1b receptor activation appeared to result from an augmentation in the accumulation of extracellular DA in the NAc induced by cocaine, a finding that suggests that 5-HT1b receptors, via stimulation by endogenous 5-HT, may have a role in cocaine reinforcement. The subsensitivity of 5-HT1b receptors during the early withdrawal phase is, therefore, interesting, not only with regard to its role in cocaine withdrawal but also with regard to the general hypothesis that dependence may result from adaptation of central reward mechanisms.
Changes In Brain Stress Systems After Chronic CocaineRecently, much attention has been directed at understanding the role of the nonneuroendocrine corticotropin-releasing factor (CRF) system in the central nucleus of the amygdala (CeA) in the affective consequences of stress and in withdrawal from drugs of abuse. The CeA is part of a complex neural circuitry regulating behavioral and autonomic responsiveness to stressful stimuli. In particular, CRF neurons in the CeA are thought to have an essential role in the mediation of emotional responses to stress, such as anxiety. Anxiety and stress-like symptoms are an integral part of drug withdrawal syndromes, raising the possibility that these withdrawal signs may involve activation of CRF neuronal mechanisms in the CeA.
Initial findings indicated that acute intraperitoneal injections of cocaine increase CRF release in the CeA of rats. This effect was significantly enhanced by 2 weeks of daily cocaine pretreatment, implicating CRF mechanisms in the CeA in cocaine sensitization as well as in the cross-sensitization between stress and psychostimulants (Richter et al. 1995). In contrast to the effects of noncontingent, intermittent cocaine administration, however, CRF release in the CeA was significantly suppressed by cocaine in self-administering rats as measured after completion of 2 weeks of cocaine self-administration training. Moreover, in these animals, cocaine withdrawal after 12 hours of continuous access to the drug produced a profound increase in CRF release, which reached peak levels of approximately 400 percent of baseline between 11 and 12 hours postcocaine (Richter and Weiss, submitted).
These data provide support for involvement of CRF mechanisms in the CeA in the motivational effects of cocaine. Central administration of CRF has stress-like anxiogenic and activational consequences in rats that can be effectively reversed by treatments that interfere with CRF transmission in the CeA. The effects of exogenous CRF resemble the behavioral signs of cocaine withdrawal in animals; these effects may be comparable to human withdrawal symptoms such as anxiety, agitation, irritability, restlessness, and confusion. Thus, the activation of CRF release in the CeA during withdrawal may provide a neurochemical basis for aspects of the cocaine abstinence syndrome. In contrast, the suppression of CRF release by cocaine during the self-administration stage may implicate attenuation of CRF release in the CeA as an element in the reinforcing actions of cocaine. Finally, these data extend previous observations on the activation of CRF mechanisms in the CeA during opiate, ethanol, and cannabinoid withdrawal and implicate enhanced amygdaloid CRF release as a common mechanism in symptoms of anxiety and negative affect that are typically associated with drug withdrawal syndromes (de Fonseca et al. 1997; Merlo Pich et al. 1995).
The evidence of a hyperactivity within an important brain stress regulatory center during cocaine withdrawal is intriguing in view of the established role of stress in drug abuse and dependence. Stress is a major determinant of relapse in humans and can increase the intake of psychostimulant drugs; it can also facilitate the acquisition of psychostimulant self-administration in laboratory animals. While many stress-associated drug-seeking behaviors may involve activation of the hypothalamic CRF system and the hypothalamic-pituitary-adrenal axis, the present data support an essential role for amygdalar CRF neurons in drug-seeking behavior motivated by stress or anxiety effects related to cocaine abstinence.
Studies examining the interaction between stress and psychostimulant withdrawal indicate that, in addition to disturbances in the brain CRF system, chronic psychostimulant exposure can disrupt normal stress responses at other levels. For example, not only did termination of daily amphetamine treatment result in a long-lasting deficit in extracellular DA concentrations in the NAc, but also stimulation of DA release in response to restraint stress, which is a typical response to this stressor in drug-naive animals, was no longer observed during amphetamine withdrawal. In fact, restraint stress produced a persistent reduction in extracellular DA concentration below basal levels that were already lowered by withdrawal from chronic amphetamine (Weiss et al., in press). Thus, certain forms of stress may exacerbate the neurochemical consequences of psychostimulant withdrawal by further lowering extracellular DA levels and, thereby, perhaps contribute to the resumption of drug-seeking behavior and increased likelihood of relapse associated with stress. Moreover, the reversal of the dopaminergic response to immobilization stress was not confined to acute abstinence but was still observed at the same magnitude 7 days postamphetamine. This persistent suppression in DA release after stress may reflect a disruption of mechanisms that regulate affective homeostasis, leading to an impairment in the ability to cope with stress or emotional challenges. Such defects may have important implications for emotional states such as depression or helplessness and for vulnerability to relapse over a prolonged abstinence period.
Chronic Cocaine And Behavioral Plasticity
The data discussed above identify perturbations in brain reward and stress systems as an important element in neuroadaptive changes induced by chronic cocaine. Another important factor associated with chronic use of cocaine (and other drugs of abuse) may involve plasticity within brain circuitries that mediate conditioning effects or stimulus-response associations. Indeed, the classical conditioning of cocaine's pharmacological effects with specific drug-associated environmental stimuli is an important aspect of its behavioral actions. Cocaine-associated stimuli can mimic the drug's locomotor-activating effects and control place preference induced by repeated pairing of cocaine injections with a specific environment. The conditioning of cocaine's rewarding actions with environmental stimuli has important implications for its abuse potential. Clinical observations suggest that stimuli previously associated with availability or self-administration of the drug can evoke intense subjective feelings of craving and can trigger episodes of relapse in abstinent cocaine abuse patients.Experimental studies of drug-seeking behavior associated with drug-related stimuli in rats indicate that incentive motivational stimuli associated with cocaine can elicit and maintain robust cocaine-seeking behavior in the absence of drug availability. For example, rats responding for presentation of conditioned stimuli previously paired with food or cocaine showed a strong shift in preference for a cocaine- over a food-associated stimulus after receiving a noncontingent "priming" injection of cocaine. This effect was particularly sensitive to reversal by a dopamine D1 antagonist, implicating activation of D1 receptors in the motivational effects of cocaine under these conditions.
In rats trained to self-administer cocaine intravenously, presentation of a discriminative stimulus previously predictive of cocaine availability elicited significant and persistent responding after extended periods of abstinence and increased DA efflux in the NAc. The reinstatement of cocaine-seeking behavior was blocked by both dopamine D1 and D2 antagonists. Together, these observations implicate activation of dopaminergic mechanisms in the motivational effects of drug-associated environmental stimuli and drug-priming. Moreover, these data suggest that cocaine-related cues may exert a "priming" action since, like cocaine, these stimuli increase extracellular levels of DA in the NAc.
SummaryIt has been proposed that drug addiction is the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse (Koob and Bloom 1988), leading to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. The results reveal perturbations in DA and 5-HT transmission in the NAc-neurochemical systems that are activated by cocaine self-administration and are deficient during withdrawal-as potential substrates for these affective changes. In addition, the results implicate neuroadaptive changes in extrahypothalamic CRF neurons and other brain stress circuitries in the motivational effects of psychostimulant withdrawal. Finally, it appears that environmental cues that become conditioned to the positive reinforcing effects of cocaine can mimic the pharmacological effect of this agent and, thereby, can initiate and maintain cocaine-seeking behavior.
AcknowledgmentThis research was supported by National Institute on Drug Abuse Grant No. DA-07348.
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Koob, G.F., and Bloom, F.E. Cellular and molecular mechanisms of drug dependence. Science 242:715- 723, 1988.
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Pich, E.M.; Lorang, M.; Yeganeh, M.; Rodriguez de Fonseca, F.; Raber, J.; Koob, G.F.; and Weiss, F. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15:5439- 5447, 1995.
Parsons, L.H.; Kerr, T.M.; Weiss, F.; and Koob, G.F. Serotonin -1B receptor stimulation enhances cocaine reinforcement: Behavioral and neurochemical studies in rats. J Neurosci, submitted.
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Weiss, F.; Imperato, A.; Casu, M.A.; Mascia, M.S.; and Gessa, G.L. Opposite effects of stress on dopamine release in the limbic system of drug-naive and chronically amphetamine-treated rats. Eur J Pharmacol 337:219- 222, 1997.
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Weiss, F.; Parsons, L.H.; and Markou, A. Neurochemistry of cocaine withdrawal. In: The Neurobiology of Cocaine: Cellular and Molecular Mechanisms. Hammer, Jr., R.L., ed. Boca Raton, FL: CRC Press, 1995. pp. 163-180.
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