Yohimbine Increases Impulsivity Through Activation of cAMP Response Element Binding in the Orbitofrontal Cortex

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• 作者：HaoSheng Sun ; Thomas A. Green ; David E.H. Theobald ; Shari G. Birnbaum ; Danielle L. Graham ; Fiona D. Zeeb ; Eric J. Nestler ; Catharine A. Winstanley
• 关键词：α ; ₂ adrenergic receptor antagonist ; ERK ; five-choice serial reaction time task ; frontal cortex ; noradrenaline ; phospho-CREB
• 刊名：Biological Psychiatry
• 出版年：2010
• 出版时间：1 April 2010
• 年：2010
• 卷：67
• 期：7
• 页码：649-656
• 全文大小：813 K

文摘

Background

Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the α₂ antagonist yohimbine is used clinically to study this aspect of the stress response. Yohimbine induces mild anxiety and increases impulsivity in healthy volunteers but has more detrimental effects in some psychiatric populations, triggering mania in bipolar patients and drug craving in substance-dependent individuals. Understanding the mechanism by which yohimbine affects brain function could provide insight into the heightened reaction to stress in these patients.

Methods

Yohimbine's effects were assessed in rats using the five-choice serial reaction time test of attention and impulse control. We then examined whether yohimbine altered activity of cyclic adenosine monophosphate response element binding (CREB) protein—a transcription factor implicated in the stress response—in brain areas that regulate impulsivity. The behavioral consequences of any changes in CREB activity were subsequently assessed using viral-mediated gene transfer to regionally overexpress CREB or the dominant negative antagonist mCREB.

Results

Yohimbine increased impulsive responding in rats and selectively increased CREB phosphorylation within the orbitofrontal cortex but not medial prefrontal cortex or nucleus accumbens. Overexpressing mCREB within the orbitofrontal cortex blocked yohimbine's effects on impulsivity, whereas overexpressing CREB in this region increased impulsive responding and potentiated the proimpulsive actions of yohimbine.

Discussion

These data suggest a novel molecular mechanism contributing to impulsivity that may be sensitive to stress. Such findings may improve our understanding of the neurobiological pathways linking the response to stress and impulsivity in both healthy and psychiatric populations.