Neuroactive Steroids in Brain and Relevance to Mood

Abstract

Depression and anxiety often affect women in relation to reproductive events like menarche, premenstrual periods, post-partum and perimenopause. A prominent example of the interaction between mood, neuroactive-steroids and the GABA system is premenstrual dysphoric disorder (PMDD). Severe premenstrual negative mood symptoms occur in 3–8% of women. Sex and stress hormones are metabolized to neuroactive steroids with effects on brain function as positive modulators of the GABA A receptor (called GABA-steroids) similar to benzodiazepines, barbiturates and alcohol. One example of a neuroactive sex steroid is allopregnanolone, and other GABA-steroids, are produced within the brain, by the adrenals at stress and from the ovary during the menstrual cycle. Animal and human studies show that benzodiazepines, barbiturates, alcohol and allopregnanolone have a bimodal effect on behavior. In high dosages or concentrations the positive GABA A receptor modulators are CNS depressants, anesthetic, and anxiolytic, whereas in certain sensitive individuals low concentrations instead of being anxiolytic cause severe anxiety, irritability, aggressiveness and depressive mood in 3–6% of individuals, and moderate symptoms in up to 30%. Low concentrations of GABA-steroids are found endogenously during the luteal phase and induce adverse emotional reactions. In women with PMDD/ PMS this paradoxical effect of neuroactive steroids seems to provoke negative mood symptoms as tension, irritability and depression. The mechanism behind the effect is called disinhibition that acts together with tolerance development by GABA A receptor active substances. Effective treatments are inhibition of ovarian steroid production or changing the CNS response to neuroactive steroids.