Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies

Abstract

Rationale Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily 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. Objectives 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.

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…Moreover, administration of 5α-dihydroprogesterone, the immediate precursor of 3α,5α-THP, to adrenalectomized rats restores effects of ethanol, showing that brain neuroactive steroid synthesis modulates effects of ethanol. Taken together, these studies suggest that elevations in neuroactive steroids influence many of the GABAergic effects of ethanol in vivo and contribute to sensitivity to behavioural effects of ethanol in rats (23, 191). …”

“…Neuroactive steroids modulate ethanol's anticonvulsant effects, sedation, impairment of spatial memory, anxiolytic-like and antidepressant-like actions (see (191) and (23) for review). Each of these behavioural responses is prevented by pre-treatment with the neuroactive steroid biosynthesis inhibitor finasteride and/or by prior adrenalectomy.…”

“…In the genetic reference population of the C57BL/6J (B6) × DBA/2J (D2) (BXD) recombinant inbred strains, basal cerebral cortical 3α,5α-THP levels across selected strains ranged between 1.81 and 3.72 ng/g, while ethanol-induced changes in cerebral cortical 3α,5α-THP ranged between +4% and +63% (23). Both basal and ethanol-induced cerebral cortical 3α,5α-THP levels in the BXD strains were correlated with some phenotypes of ethanol intake, suggesting that neuroactive steroid responses to ethanol may be associated with excessive alcohol consumption (23). …”

“…The neuroactive steroid response to stress is a complex phenomenon that involves adaptations in GABA A receptor plasticity and appears to differ across species (for recent reviews see (23, 48)).…”

Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder

“…Similarly, several lines of evidence point to changes in GABAergic activity that accompany alterations in steroid hormone milieu (Bäckström et al 2003). Both the density and subunit composition of GABA A receptors in the central nervous system vary over the estrous cycle in response to fluctuations in neurosteroid levels (Maguire et al 2005, Maguire et al 2007, Maguire et al 2009, and Porcu et al 2014). …”