Yohimbine increases impulsivity through activation of cAMP response element binding in the orbitofrontal cortex.
BACKGROUND
Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the alpha(2) 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.


CONCLUSIONS
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.
Sun
HaoSheng
H
Department of Psychology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
Green
Thomas A
TA
Theobald
David E H
DE
Birnbaum
Shari G
SG
Graham
Danielle L
DL
Zeeb
Fiona D
FD
Nestler
Eric J
EJ
Winstanley
Catharine A
CA
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects*; D050882:CREB-Binding Protein / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects; D015016:Yohimbine / Q000008:administration & dosage / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D015016:Yohimbine; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D009638:Norepinephrine