Context-dependent and -independent effects of D1 receptor antagonism in the basolateral and central amygdala during cocaine self-administration

Abstract One way that drugs of abuse perturb the dopamine system is by triggering large amounts of extracellular dopamine efflux into limbic regions. The basolateral (BLA) and central (CeA) nuclei of the amygdala have been shown to play distinct roles in value representation of primary and conditioned reward. However, the precise role of dopaminergic receptors in the BLA and the CeA during reward-related behaviors remains to be determined. Here we investigate the effects of dopamine D1 receptor blockade in the BLA and the CeA during asymptotic performance of cocaine self administration and in a novel application of contextual renewal under continued access conditions. After >3 weeks of chained seek-take self-administration of cocaine, male Long Evans rats were given a bilateral intra-BLA or intra-CeA infusion of the D1 antagonist SCH-23390 (2 µg/0.3 µL) for multiple days. Intra-BLA D1 receptor blockade before, but not after the self-administration session, gradually suppressed drug seeking and taking responses and persisted with a change in context with continued D1 blockade. In contrast, intra-CeA D1 receptor blockade caused a rapid reduction in self-administration that showed renewal with a change in context with continued D1 blockade. Further, conditioned place aversion developed with intra-BLA but not intra-CeA infusions. Collectively, these results demonstrate that dopamine D1 receptors in the BLA and CeA both contribute to drug seeking and taking, but may do so through distinct mechanisms. Significance Statement Drugs of abuse perturb the dopamine system by triggering large amounts of dopamine to efflux into limbic regions. The basolateral (BLA) and central (CeA) nuclei of the amygdala play distinct roles in value representation of primary and conditioned reward. However, the precise role of dopaminergic receptors in the BLA and the CeA during reward-related behaviors remains to be determined. Here we show that D1 antagonism in the BLA and CeA suppressed cocaine seeking and taking behavior, but only the BLA effect resisted contextual renewal. This study provides evidence for a novel method to weaken the effects of cocaine itself during active drug self-administration, and thereby provides insights into possible therapeutic interventions that may help prevent relapse.