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

Abstract

Background The neurosteroid allopregnanolone is a potent allosteric modulator of the GABA(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 400mg of pregnenolone (N=16) or placebo (N=15) and underwent 3T fMRI while performing the Shifted-Attention Emotion Appraisal Task (SEAT), which probes emotional processing and regulation. Results Compared to 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 pharmacological intervention in the treatment of anxiety disorders, and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

“…Third, during an emotional appraisal task in healthy men treated with pregnenolone, increased allopregnanolone plasma levels were accompanied by altered connectivity between the medial PFC and the amygdala, components of a circuit implicated as dysfunctional in depression (Sripada et al, 2013). Fourth, postmortem studies observed decreased 5α-reductase mRNA expression in the PFC of depressed men and women compared with non-depressed controls (Agis-Balboa et al, 2014).…”

A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression

“…More recent work has suggested that pregnenolone and its metabolites modulate functional connectivity in the human amygdala (Sripada et al, 2014) and enhance activation of neurocircuits pertinent to mood and emotions (Sripada et al, 2013). Clinical trials suggest that pregnenolone and its derivatives, such as allopregnanolone, have potential in treating schizophrenia (Marx et al, 2009;Ritsner et al, 2010;Zorumski et al, 2013b).…”

“…A small study that included both unipolar and bipolar depressed patients suggested improvement in depressive symptoms with pregnenolone (100 mg/day) as compared with placebo (Osuji et al, 2010). Given these data, pregnenolone and other neurosteroids have been suggested as potential therapeutic targets for neuropsychiatric disorders (Sripada et al, 2013;Torrey and Davis, 2012;Zorumski and Mennerick, 2013a;Zorumski et al, 2013b).…”

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

“…In support of the hypothesis that allopregnanolone and pregnanolone have anxiolytic properties, two small studies suggest that the plasma concentrations of pregnenolone sulfate, a precursor of these steroids, is lower in males with generalized social phobia or GAD (Semeniuk et al, 2001;Heydari and Le Mellédo, 2002). Administration of pregnenolone is associated with an increase in allopreganolone and reduced activity in the amygdala and insula, as well as a reduction in self-reported anxiety (Sripada et al, 2013) (Fig. 10).…”