Yohimbine impairs extinction of cocaine-conditioned place preference in an alpha2-adrenergic receptor independent process.

Davis AR, Shields AD, Brigman JL, Norcross M, McElligott ZA, Holmes A, Winder DG
Learn Mem. 2008 15 (9): 667-76

PMID: 18772254 · PMCID: PMC2632785 · DOI:10.1101/lm.1079308

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 alpha(2)-adrenergic receptor (alpha(2)-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 alpha(2)-AR antagonist yohimbine impaired cocaine CPP extinction in C57BL/6J mice, an effect that was not mimicked by the more selective alpha(2)-AR antagonist, atipamezole. Moreover, alpha(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 alpha(2A)-AR knockout mice. Our data strongly suggest that extinction-modifying effects of yohimbine are unlikely to be due to actions at alpha(2A)-ARs.

MeSH Terms (15)

Adrenergic alpha-Antagonists Amygdala Animals Cocaine Conditioning (Psychology) Dopamine Uptake Inhibitors Extinction, Psychological Imidazoles Male Mice Mice, Inbred C57BL Mice, Knockout Patch-Clamp Techniques Receptors, Adrenergic, alpha-2 Yohimbine

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