Yohimbine impairs extinction of cocaine-conditioned place preference in an alpha2-adrenergic receptor independent process.
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.
Davis
Adeola R
AR
Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615, USA.
Shields
Angela D
AD
Brigman
Jonathan L
JL
Norcross
Maxine
M
McElligott
Zoe A
ZA
Holmes
Andrew
A
Winder
Danny G
DG
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D018765:Dopamine Uptake Inhibitors; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D015016:Yohimbine; D003042:Cocaine
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