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Allopregnanolone Mediates Affective Switching Through Modulation of Oscillatory States in the Basolateral Amygdala

      Abstract

      Background

      Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABAA (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects.

      Methods

      We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states.

      Results

      We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABAA receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6–12 Hz) through δ-containing GABAA receptors, a mechanism distinct from other GABAA positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress–induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress.

      Conclusions

      Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

      Keywords

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      Linked Article

      • Mechanisms Underlying Recovery From Postpartum Depression Following Brexanolone Therapy
        Biological PsychiatryVol. 91Issue 3
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          The remarkable efficacy, rapid therapeutic response, and long-lasting effects of brexanolone for the treatment of postpartum depression (1) represent a major advance in the field of psychiatry and provide hope for treatment of many other conditions that share similar phenotypes of anxiety, dysphoria, irritability, and despair. These symptom profiles are not unique to postpartum depression, but instead are shared by many neuropsychiatric syndromes with varied primary diagnostic criteria as narrow as specific types of anxiety and depression, or as broad as pain, posttraumatic stress, substance abuse, and psychoses.
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