Yohimbine impairs extinction of cocaine-conditioned place preference in an α₂-adrenergic receptor independent process

Abstract

Extinction, a form of learning that has the ability to reshape learned behavior based on new experiences, has been heavily studied utilizing fear learning paradigms. Mechanisms underlying extinction of positive-valence associations, such as drug self-administration and place preference, are poorly understood yet may have important relevance to addiction treatment. Data suggest a major role for the noradrenergic system in extinction of fear-based learning. Employing both pharmacological and genetic approaches, we investigated the role of the α₂-adrenergic receptor (α₂-AR) in extinction of cocaine-conditioned place preference (CPP) and glutamatergic transmission in the bed nucleus of the stria terminalis (BNST). We found that pre-extinction systemic treatment with the α₂-AR antagonist yohimbine impaired cocaine CPP extinction in C57BL/6J mice, an effect that was not mimicked by the more selective α₂-AR antagonist, atipamezole. Moreover, α_2A-AR knockout mice exhibited similar cocaine CPP extinction and exacerbated extinction impairing effects of yohimbine. Using acute brain slices and electrophysiological approaches, we found that yohimbine produces a slowly evolving depression of glutamatergic transmission in the BNST that was not mimicked by atipamezole. Further, this action was extant in slices from α_2A-AR knockout mice. Our data strongly suggest that extinction-modifying effects of yohimbine are unlikely to be due to actions at α_2A-ARs.