Article

Yohimbine impairs extinction of cocaine-conditioned place preference in an 2-adrenergic receptor independent process

Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615, USA.
Learning & memory (Cold Spring Harbor, N.Y.) (Impact Factor: 3.66). 02/2008; 15(9):667-76. DOI: 10.1101/lm.1079308
Source: PubMed

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 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.

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Available from: Angela D Shields, Jan 13, 2014
    • "However , when the data were reanalyzed to control for initial preference, a high dose of prazosin accelerated extinction in animals with a high initial preference score (Bernardi and Lattal, 2012b). Yohimbine impaired the extinction of cocaine CPP, although this effect was not replicated with a selective a2AR antagonist and may be mediated by orexin rather than NE (Davis et al., 2008; Conrad et al., 2012). "
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    ABSTRACT: Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). While stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, non-human primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to 5 stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms, but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.
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    • "There have been several interesting observations regarding the influence of noradrenergic mechanisms on the extinction of drug-seeking behavior. Yohimbine, an alpha2-receptor antagonist that promotes the release of norepinephrine, impairs the extinction of cocaine CPP (Davis et al., 2008) and slows the rate of extinction of cocaine self-administration (Kupferschmidt et al., 2009). Furthermore, infusion of the beta-receptor agonist clenbuterol into the IfL cortex facilitates extinction of cocaine-seeking behavior (LaLumiere et al., 2010). "
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    • "The drug effects on extinction may differ based on the arousal-inducing properties of the paradigm. For example , yohimbine failed to affect extinction of a cocaine CPP (Davis et al., 2008), but it facilitated the extinction of fear conditioning (Morris and Bouton, 2007). The emotional arousal during drug cue-association paradigms like CPP or cue-induced responding may be relatively weak compared to arousal during fear conditioning. "
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