Neural substrates of cocaine-cue associations that trigger relapse

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Abstract

Learned associations that occur during the process of repeated drug use in addiction can later manifest as trigger factors in relapse to renewed drug-seeking and drug-taking behavior. The process of conditioned-cued relapse of drug-seeking behavior has been successfully modeled in animals using the reinstatement procedure, in which chronic drug self-administration can be extinguished or withheld, and then reinstated using conditioned stimuli previously paired with the drug. Our laboratory has extensively studied the neural circuitry underlying conditioned-cued drug-seeking during the expression of reinstatement. In order to study the learning process of drug-cue pairings, we further developed a procedure whereby discrete cocaine-cue pairings can be conducted in a single pavlovian training session in animals previously trained to self-administer cocaine. Presentation of these cues during later reinstatement trials produces robust responding over extinction levels at levels similar to those seen when animals experience the cues on a daily basis. In a series of experiments, we have shown that reversible pharmacological inactivation of the basolateral complex of the amygdala just prior to acquisition of cocaine-cue associations blocks the ability of cocaine-paired stimuli to elicit conditioned-cued reinstatement. This learning process is mediated in part by muscarinic acetylcholine and dopaminergic inputs to the basolateral complex of the amygdala, as intra-amygdala infusion of selective receptor antagonists at the time of acquisition significantly affects reinstatement. We have also recently found that disruption of neural activity within the basolateral complex of the amygdala at the time of consolidation (just after cocaine-cue pairings) will disrupt reinstatement. Taken together, these results reveal the importance of the amygdala in the acquisition, consolidation, and expression of drug-stimulus learning that drives relapse to drug-seeking behavior.

Section snippets

Conditioned cues and relapse to drugs of abuse

Drug dependence is characterized by high rates of relapse to drug-seeking and drug-taking behavior following periods of abstinence and drug detoxification. While multiple trigger factors can initiate or sustain relapse, evidence has clearly established the ability of drug-associated environmental cues (e.g., associated drug paraphernalia or locations where a drug was previously consumed) to elicit drug craving, and consequently reinstate drug-seeking and drug-taking. Conditioned-cued responses

Animal models of conditioned-cued relapse

Craving as an operationally defined construct presents a major challenge to establish and measure using animal models of addiction (Littleton, 2000, Markou et al., 1993). However, animal models can clearly provide a variety of objective and quantifiable indices of drug-seeking behavior. The well established self-administration paradigm in laboratory animals (Weeks, 1962) has provided an empirical model to study multiple factors in drug-taking behavior, particularly in regards to the acquisition

Associative learning with drugs of abuse

Chronic drug self-administration involves multiple exposures to the drug-taking environment and all of the specific stimuli associated with the drug-taking experience over periods of days to weeks. Thus, there has been limited focus on the specific phases of drug-stimulus learning. In contrast, a number of animal models of aversive conditioning have extensively examined the separate mnemonic processes of acquisition, consolidation, and expression of discrete conditioned associations (Davis et

Neural substrates of drug-cue associations

Several lines of research have extensively implicated the amygdala in the acquisition and expression of a variety of motivational tasks, both aversive (Cahill and McGaugh, 1990, LeDoux, 2000) and appetitive (Everitt et al., 2000, Gallagher and Chiba, 1996). In our initial studies, we focused extensively on the role of the basolateral complex of the amygdala in reinstatement using animals with an extensive history of drug-cue pairings (i.e., each day of drug self-administration included discrete

Extending the circuitry of drug-cue associations

Most of our previous work using the reinstatement model of relapse has focused on amygdalar mediation of drug-stimulus associative learning that contributes to reinstatement of drug-seeking behavior. The amygdala has widespread connections with a number of forebrain structures, including extensive glutamatergic efferent projections to the nucleus accumbens and prefrontal cortex (Brinley-Reed et al., 1995, McDonald, 1991, Sesack et al., 1989). In regards to the expression of reinstatement, we

Acknowledgement

The authors' work is supported by the National Institute on Drug Abuse (DA10462, DA15369, DA16511).

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