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Randomized Controlled Trial
, 73 (11), 1045-53

Allopregnanolone Elevations Following Pregnenolone Administration Are Associated With Enhanced Activation of Emotion Regulation Neurocircuits

Affiliations
Randomized Controlled Trial

Allopregnanolone Elevations Following Pregnenolone Administration Are Associated With Enhanced Activation of Emotion Regulation Neurocircuits

Rebecca K Sripada et al. Biol Psychiatry.

Abstract

Background: The neurosteroid allopregnanolone is a potent allosteric modulator of the gamma-aminobutyric acid type A receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry.

Methods: To investigate the brain basis of allopregnanolone's impact on emotion regulation, participants were administered 400 mg of pregnenolone (n=16) or placebo (n=15) and underwent 3T functional magnetic resonance imaging while performing the shifted-attention emotion appraisal task, which probes emotional processing and regulation.

Results: Compared with placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety.

Conclusions: These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

Conflict of interest statement

The remaining authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1
Figure 1
Task stimuli depict neutral, angry, or fearful expressions superimposed on building pictures of indoor or outdoor scenes. Faces reprinted with permission from the Paul Ekman Group, LLC.
Figure 2
Figure 2
(A) Compared to placebo, pregnenolone administration decreased activation in right amygdala (y=2) and right insula (z=-6) across conditions and face types. (B) Compared to placebo, pregnenolone administration increased dorsal medial prefrontal cortex activation during appraisal (x=0). Percent signal change is displayed next to each figure. PREG=pregnenolone administration group. PBO=placebo.
Figure 3
Figure 3
Pregnenolone administration increased functional connectivity between dorsal medial prefrontal cortex (dmPFC) and left amygdala (y=3) during appraisal. PREG=pregnenolone administration group. PBO=placebo.

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