Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies.
BACKGROUND
Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily γ-aminobutyric acid type A (GABAA) receptors. Neuroactive steroids regulate many physiological processes including hypothalamic-pituitary-adrenal (HPA) axis function, ovarian cycle, pregnancy, aging, and reward. Moreover, alterations in neuroactive steroid synthesis are implicated in several neuropsychiatric disorders.


OBJECTIVE
This review will summarize the pharmacological properties and physiological regulation of neuroactive steroids, with a particular focus on divergent neuroactive steroid responses to stress and ethanol in rats, mice, and humans.


RESULTS
GABAergic neuroactive steroids exert a homeostatic regulation of the HPA axis in rats and humans, whereby the increase in neuroactive steroid levels following acute stress counteracts HPA axis hyperactivity and restores homeostasis. In contrast, in C57BL/6J mice, acute stress decreases neurosteroidogenesis and neuroactive steroids exert paradoxical excitatory effects upon the HPA axis. Rats, mice, and humans also differ in the neuroactive steroid responses to ethanol. Genetic variation in neurosteroidogenesis may explain the different neuroactive steroid responses to stress or ethanol.


CONCLUSIONS
Rats and mouse strains show divergent effects of stress and ethanol on neuroactive steroids in both plasma and brain. The study of genetic variation in the various processes that determine neuroactive steroids levels as well as their effects on cell signaling may underlie these differences and may play a relevant role for the potential therapeutic benefits of neuroactive steroids.
Neuroscience Institute, National Research Council of Italy (CNR), Cittadella Universitaria, 09042, Monserrato, Cagliari, Italy, patrizia.porcu@in.cnr.it.
Patrizia
P
Porcu
A Leslie
AL
Morrow
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D013045:Species Specificity; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology
D002492:Central Nervous System Depressants; D018377:Neurotransmitter Agents; D000431:Ethanol; D005680:gamma-Aminobutyric Acid