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

Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

“…In particular, the BNST is critical for yohimbineinduced reinstatement of drug-seeking behavior (Brown et al, 2009;Buffalari and See, 2010). Yohimbine depresses excitatory transmission in the adult dorsal BNST (Davis et al, 2008). This finding is paradoxical given that a 2 -AR agonists produce similar actions (Davis et al, 2008;Shields et al, 2009).…”

“…This finding is paradoxical given that a 2 -AR agonists produce similar actions (Davis et al, 2008;Shields et al, 2009). Further, the effects of yohimbine on both excitatory transmission and extinction of cocaine-CPP are intact in a 2A -AR knockout mice and not fully mimicked by the a 2 -AR antagonist atipamezole, suggesting that they are mediated by targets other than a 2 -ARs (Davis et al, 2008).…”

“…Moreover, 5 mg/kg but not 1 mg/kg yohimbine induces Fos expression in the lateral BNST (Myers et al, 2005). Finally, other studies in C57Bl/6J mice (Cain et al, 2004;Hefner et al, 2008), as well as a previous study from our lab (Davis et al, 2008) have found the 5 mg/kg dose effective at altering fear and anxietyrelated behaviors.…”

“…Yohimbine is thought to act primarily via its inhibition of presynaptic noradrenergic alpha2 adrenergic receptor (a 2 -ARs), thereby increasing norepinephrine levels (Abercrombie et al, 1988;Aghajanian and VanderMaelen, 1982;Starke, 2001). In addition to research using yohimbine as a pharmacological stressor to induce illicit drug-and alcohol-reinstatement (Shaham et al, 2000;Shalev et al, 2010), recent studies demonstrate yohimbine impairs extinction of cocaineconditioned place preference (cocaine-CPP) and self-administration (Davis et al, 2008;Kupferschmidt et al, 2009;Marinelli et al, 2007).…”

Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

“…Of note, yohimbine has been shown to slow extinction of cocaine behaviors (Davis et al 2008;Kupferschmidt et al, 2009), which could pose a significant therapeutic limitation; yet, following repeated administration, a reduced capacity to produce a subsequent reinstatement has been observed (Kupferschmidt et al, 2009). Thus, a certain amount of arousal may be required to establish lasting extinction memories, which if carefully monitored within a clinical setting, may permit drugs such as atomoxetine to safely promote abstinence.…”