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

Hao Sheng Sun, Thomas A. Green, David E.H. Theobald, Shari G. Birnbaum, Danielle L. Graham, Fiona D. Zeeb, Eric J. Nestler, Catharine A. Winstanley

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)649-656
Number of pages8
JournalBiological Psychiatry
Issue number7
StatePublished - Apr 1 2010
Externally publishedYes


  • ERK
  • five-choice serial reaction time task
  • frontal cortex
  • noradrenaline
  • phospho-CREB
  • α adrenergic receptor antagonist

ASJC Scopus subject areas

  • Biological Psychiatry


Dive into the research topics of 'Yohimbine Increases Impulsivity Through Activation of cAMP Response Element Binding in the Orbitofrontal Cortex'. Together they form a unique fingerprint.

Cite this