Neurobiological mechanisms of relapse

Relapse of drug-seeking behavior in drug-dependent subjects is often precipitated by drug-associated stimuli, or low doses of the drug itself. In animals, relapse of drug-seeking behavior can be induced by experimental activation of the mesolimbic dopamine system, leading to activation of dopamine receptors in the nucleus accumbens. We used a drug “reinstatement” paradigm to study the pharmacological and intracellular stimuli that induce relapse of drug-seeking behavior in rats following extinction of intravenous cocaine self-administration. Relapse of cocaine-seeking behavior was prominently induced by systemic injections of D2-like, and not by D1-like, dopamine receptor agonists, despite similar locomotor stimulant properties of the drugs. More importantly, pretreatment with D1-like receptor agonists completely abolished the ability of cocaine itself to induce relapse of cocaine-seeking behavior, while D2-like receptor agonists enhanced this ability, suggesting that D2-like agonists may be useful as a novel replacement pharmacotherapy for the treatment of cocaine addiction. Since dopamine receptors exert opposing modulatory influences on intracellular cyclic AMP levels, we tested the role of cyclic AMP-dependent protein kinase (PKA) in the nucleus accumbens in relapse of cocaine-seeking behavior. Bilateral intra-accumbens infusions of a PKA inhibitor, but not a PKA activator, induced relapse of cocaine-seeking behavior, and enhanced the ability of cocaine itself to induce relapse. These results suggest that acute activation of D2-like dopamine receptors leads to decreased PKA activity in the nucleus accumbens that may underlie drug craving and relapse in drug-dependent subjects.