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


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
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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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    ABSTRACT: Theories of drug addiction that incorporate various concepts from the fields of learning and memory have led to the idea that classical and operant conditioning principles underlie the compulsiveness of addictive behaviors. Relapse often results from exposure to drug-associated cues, and the ability to extinguish these conditioned behaviors through inhibitory learning could serve as a potential therapeutic approach for those who suffer from addiction. This review will examine the evidence that extinction learning alters neuronal plasticity in specific brain regions and pathways. In particular, subregions of the prefrontal cortex (PFC) and their projections to other brain regions have been shown to differentially modulate drug-seeking and extinction behavior. Additionally, there is a growing body of research demonstrating that manipulation of neuronal plasticity can alter extinction learning. Therefore, the ability to alter plasticity within areas of the PFC through pharmacological manipulation could facilitate the acquisition of extinction and provide a novel intervention to aid in the extinction of drug-related memories.
    Frontiers in Psychiatry 05/2013; 4(46):46. DOI:10.3389/fpsyt.2013.00046
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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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    ABSTRACT: Cues associated with alcohol can stimulate subjective states that increase relapse. Alcohol-cue associations may be strengthened by enhancing adrenergic activity with yohimbine or weakened by blocking adrenergic activity with propranolol. Alcohol-cue associations may also be weakened by long cue exposure sessions or strengthened by short cue exposure sessions. A useful treatment approach for alcoholism may combine adrenergic manipulation with cue exposure sessions of a specific duration. The present study sought to determine if cue exposure during long- or short-duration extinction sessions with post-session yohimbine or propranolol would alter alcohol cue-induced responding and self-administration. Rats were trained to respond for alcohol during sessions that included an olfactory cue given at the beginning of the session and a visual/auditory cue complex delivered concurrently with alcohol. Cue-induced responding was assessed before and after the repeated extinction sessions. Repeated alcohol extinction sessions of long duration (45 min) or short duration (5 min) were followed immediately by injections of saline, yohimbine, or propranolol. After the second set of cue-induced responding tests, reacquisition of operant alcohol self-administration was examined. To determine if the experimental procedures were sensitive to memory manipulation through other pharmacological mechanisms, the NMDA receptor antagonist MK-801 was given 20 min prior to long-duration extinction sessions. Both the long- and short-duration extinction sessions decreased cue-induced responding. Neither yohimbine nor propranolol, given post-session, had subsequent effects on cue-induced responding or alcohol self-administration. MK-801 blocked the effect of extinction sessions on cue-induced responding but had no effect on self-administration. The present study shows that manipulation of the NMDA system in combination with alcohol cue exposure therapy during extinction-like sessions may be more effective than manipulation of the adrenergic system in reducing the strength of alcohol-cue associations in this specific model of alcohol relapse.
    Pharmacology Biochemistry and Behavior 01/2013; 116. DOI:10.1016/j.pbb.2013.11.020 · 2.78 Impact Factor
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    • "Pavlovian fear conditioning and extinction was assessed as described previously [32,33]. The mouse was placed in context A: a 270 × 270 × 110 mm chamber with transparent walls and a metal rod floor. "
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    ABSTRACT: Potassium channels have been proposed to play a role in mechanisms of neural plasticity, and the Kv4.2 subunit has been implicated in the regulation of action-potential back-propagation to the dendrites. Alterations in mechanisms of plasticity have been further proposed to underlie various psychiatric disorders, but the role of Kv4.2 in anxiety or depression is not well understood. In this paper, we analyzed the phenotype Kv4.2 knockout mice based on their neurological function, on a battery of behaviors including those related to anxiety and depression, and on plasticity-related learning tasks. We found a novelty-induced hyperactive phenotype in knockout mice, and these mice also displayed increased reactivity to novel stimulus such as an auditory tone. No clear anxiety- or depression-related phenotype was observed, nor any alterations in learning/plasticity-based paradigms. We did not find clear evidence for an involvement of Kv4.2 in neuropsychiatric or plasticity-related phenotypes, but there was support for a role in Kv4.2 in dampening excitatory responses to novel stimuli.
    Biology of Mood and Anxiety Disorders 03/2012; 2(1):5. DOI:10.1186/2045-5380-2-5
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