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Dopaminergic Mechanisms in Relapse to Cocaine‐Seeking Behavior: Implications for Medications Development

Development of preclinical models that simulate relevant features of cocaine use and relapse in people is crucial for identifying neurobiological processes underlying cocaine addiction and for developing effective therapeutic interventions. We have adapted i.v. drug self administration techniques in nonhuman primates to investigate environmental and pharmacological triggers of relapse to cocaine-seeking behavior and to evaluate potential pharmacological strategies for relapse prevention. Squirrel monkeys initially received extended histories of i.v. cocaine self-administration under conditions in which drug-seeking behavior was maintained jointly by cocaine injections and by presentations of a cocaine-paired environmental stimulus (secondorder schedule). Drug seeking subsequently was extinguished by substituting vehicle for cocaine and by omitting the cocaine-paired stimulus. Reinstatement of extinguished drug-seeking could be induced reliably by noncontingent administration of cocaine (priming) or by contingent presentations of the cocaine-paired stimulus, with maximum effects observed when the two triggering events were combined. Drugs that share cocaine’s indirect dopamine (DA) agonist properties (e.g., methamphetamine) or that act as direct D 2 -like receptor agonists (e.g., propylnorapomorphine, quinipirole) also induced robust cocaine-seeking behavior, whereas D 1 -like receptor agonists (e.g., SKF 82958, SKF 81297) and preferential D 3 receptor agonists (PD128,907,7-OH-DPAT) did not reliably induced drug-seeking. This pharmacological profile differs from profiles observed in corresponding studies involving drug discrimination or drug self-administration paradigms, implying that the relapse-inducing, subjective, and reinforcing effects of cocaine reflect dissociable neurobiological processes. Antagonists and partial agonists at both D 1 -like (SCH39166,SKF 38359) and D 2 -like receptors (nemonapride, eticlopride, terguride, SDZ 208-911) dose-dependently attenuated reinstated of drug-seeking induced by a cocaine prime. Similar effects also were observed with D 1 -like, but not D 2 -like receptor full agonists. The results suggest that medications capable of modulating DA (notably D 1 ) receptor activity may be attractive candidates for investigation as anti-relapse pharmacotherapies.