Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior

Activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to elevations in γ-aminobutyric acid (GABA)-ergic neuroactive steroids that enhance GABA neurotransmission and restore homeostasis following stress. This regulation of the HPA axis maintains healthy brain function and protects against neuropsychiatric disease. Ethanol sensitivity is influenced by elevations in neuroactive steroids that enhance the GABAergic effects of ethanol, and may prevent excessive drinking in rodents and humans. Low ethanol sensitivity is associated with greater alcohol consumption and increased risk of alcoholism. Indeed, ethanol-dependent rats show blunted neurosteroid responses to ethanol administration that may contribute to ethanol tolerance and the propensity to drink greater amounts of ethanol. The review presents evidence to support the hypothesis that neurosteroids contribute to ethanol actions and prevent excessive drinking, while the lack of neurosteroid responses to ethanol may underlie innate or chronic tolerance and increased risk of excessive drinking. Neurosteroids may have therapeutic use in alcohol withdrawal or for relapse prevention.