Neuroactive Steroids: Effects on Cognitive Functions

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.