Drug addiction, relapse, and the amygdala.

Evidence has extensively implicated the amygdala in the associative learning process for appetitive reinforcers. Recent interest has focused on the role of the amygdala in the learned associations that occur during the process of drug addiction and relapse. Using an animal model of relapse after chronic cocaine self-administration, we found that rats reinstate extinguished lever responding for conditioned stimuli (tone + light) previously paired with cocaine or heroin ("conditioned-cued reinstatement"). The basolateral amygdala (BLA) complex plays a critical role in this behavior, because permanent lesions or reversible pharmacologic inactivation of the BLA attenuates conditioned-cued reinstatement without affecting cocaine self-administration or cocaine-primed reinstatement. Conditioned-cued reinstatement appears to be mediated in part by dopamine inputs to the BLA, as intra-BLA infusion of a dopamine D1 receptor antagonist blocks reinstatement, whereas intra-BLA infusion of amphetamine potentiates reinstatement. Furthermore, the BLA is also necessary for acquisition of associative learning with cocaine-paired stimuli. Disruption of neural activity within the BLA by sodium channel blockade or muscarinic receptor blockade just before acquisition of stimulus-cocaine associations blocks the ability of conditioned stimuli to elicit conditioned-cued reinstatement after extinction. Together, these results reveal the importance of the amygdala as part of a corticolimbic circuit mediating both the acquisition and the expression of conditioning that plays a critical role in relapse to drug-seeking behavior.