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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 GABAA 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 GABAA 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 GABAA receptor active substances. Effective treatments are inhibition of ovarian steroid production or changing the CNS response to neuroactive steroids. [ABSTRACT FROM AUTHOR]

Dementia and Alzheimer's disease afflict approximately 5% of the population over 65, and > 20% of the population > 80. These disorders are likely to increase substantially given the change in the demographic pattern. The cost for the society and suffering for the families are tremendous. Stress and disorders with increased production of steroids seem to induce cognitive impairment. Likewise drugs that induce high activity in the Gamma Amino Butyric Acid-A (GABAA) receptor seem to be involved in dementia development and cognitive impairment. This review will concentrate on arguments indicating a link between stress disordersneuroactive steroids active on the GABAA receptor (GABA-steroids) and permanent cognitive impairment. Chronic long-term exposure by all GABAA receptor agonists, e.g., benzodiazepines, barbiturates and alcohol, give permanent memory and learning impairment. The sex-steroid medroxyprogesterone, given as postmenopausal hormone therapy, double the dementia frequency in 5 years. The neuroactive steroid allopregnanolone inhibits learning in rat studies. Chronically high cortisol and GABA-steroid levels give irreversible cognitive damages. During stress the production of both cortisol and GABA-steroids increase in parallel. GABA-steroid production occurs in the adrenals and are produced and regulated as cortisol. Patients with advanced Alzheimer's disease have similar cortisol and GABA-steroid response to adrenal stimulation as chronically stressed animals. Patients with mild Alzheimer's disease have a high and non-suppressible production of cortisol and GABA-steroids. Cortisol metabolites increase the effect of allopregnanolone on the GABAA receptor. Chronic stress and "burn-out syndrome" gives permanent cognitive damages and are frequent in the patient history of patients with Alzheimer's disease. An impaired cholinergic system is involved in Alzheimer's disease. Allopregnanolone hamper memory-related cholinergic action. GABAA receptor subunit alpha5 is mainly localized in the hippocampus, i.e., in the region for learning and memory. Blockade of the GABAA receptor subunit alpha5 increased learning and memory. An allopregnanolone antagonist is shown to antagonize the learning and memory disruption of allopregnanolone both in vitro in receptor pharmacological studies and in vivo in studies using the Morris Water Maze model. [ABSTRACT FROM AUTHOR]