Yohimbine increases impulsivity through activation of cAMP response element binding in the orbitofrontal cortex

Abstract

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.

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.

Figure 1. The effects of yohimbine on 5CSRT performance

Yohimbine significantly increased premature responding on the 5CSRT (panel A). Accuracy of target detection was unaffected by the drug, whereas lower doses decreased omissions. Data shown are mean ± SEM. * indicates a significant difference (p< 0.05) as determined by one-way ANOVA comparing vehicle to drug dose.

Figure 2. Western blot analysis of protein expression within the OFC, mPFC and NAc 30 mins after yohimbine administration

Yohimbine selectively increased phosphorylation of CREB and ERK42 in the OFC, but not in the mPFC or NAc. No change in the levels of unphosphorylated proteins were observed. Data are shown as the mean fold change from control ± SEM. * indicates a significant difference (p< 0.05), # indicates a trend level of significance (p< 0.1) as determined by independent samples Student's t-tests.

Figure 3. Over-expressing CREB within the OFC increases premature responding in the 1CSRT

As shown in panel A, a transient increase in premature responding was observed in animals over-expressing CREB within the OFC during the first week of post-operative testing, whereas over-expressing mCREB did not affect performance. In contrast, behaviour was not altered by increasing levels of CREB or mCREB within the NAc (panel B). Data are presented as the average from each week of post-operative testing. * indicates a significant difference (p< 0.05) from control.

Figure 4. Modulating CREB activity within the OFC, but not the NAc, affects the increase in premature responding caused by yohimbine

Yohimbine increased premature responding in control animals, and this effect was potentiated in rats over-expressing CREB within the OFC and attenuated in those over-expressing mCREB within this region (panel A). Over-expression of CREB or mCREB within the NAc did not affect the response to yohimbine (panel B), with both groups showing a drug-induced increase in premature responding comparable to the control group. * indicates a significant within-group difference (p< 0.05) as determined by one-way ANOVA comparing vehicle to drug dose. # indicates a significant between-group difference (p< 0.05) as compared to GFP controls via independent samples Student's t-tests.