Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies - PubMed (original) (raw)

Review

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

Patrizia Porcu et al. Psychopharmacology (Berl). 2014 Sep.

Abstract

Rationale: 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.

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.

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Figures

Figure 1

Schematic representation of the putative mechanisms and sites of action of GABAergic neuroactive steroids. Neuroactive steroids, such as 3α,5α-THP and 3α,5α-THDOC, exert inhibitory actions mediated by synaptic and extrasynaptic GABAA receptors. No active release mechanism has been identified for endogenous neuroactive steroids. They may access the neuroactive steroid transmembrane binding sites via paracrine (a) or autocrine (b) mechanisms or by intracellular lateral diffusion through the cell membrane (c). There is also evidence for extracellular pockets of neuroactive steroid storage that allow for rapid and repeated access to extracellular binding sites on neurons. These effects are described and referenced in the text.

Figure 2

Variation in basal and ethanol-induced 3α,5α-THP across selected BXD strains. Group-housed male mice (8 to 12 weeks old) were injected with saline (basal levels) or ethanol (2 g/kg, i.p.) at 9:00 am and were euthanized 1 hour later. 3α,5α-THP levels were measured in the cerebral cortex by radioimmunoassay. (a) Data are expressed as ng/g of tissue and are means ± SEM of values from 3-16 mice per strain. (b) Data are expressed as percent change of the average 3α,5α-THP levels in the ethanol-treated group vs. the average 3α,5α-THP levels in the respective saline-treated group (n = 3-16/group/strain).

Figure 3

Genetic correlations between basal or ethanol-induced 3α,5α-THP levels and behavioral phenotypes for ethanol consumption previously characterized in the BXD strains. Group-housed male mice (8 to 12 weeks old) were injected with saline (basal levels) or ethanol (2 g/kg, i.p.) at 9:00 am and were euthanized 1 hour later. 3α,5α-THP levels were measured in the cerebral cortex by radioimmunoassay. Data are expressed as ng/g of tissue (basal levels) or as percent change of the average 3α,5α-THP levels in the ethanol-treated group vs. the average 3α,5α-THP levels in the respective saline-treated group (n = 3-16/group/strain). Behavioral data for ethanol consumption has been collected by independent labs and has been obtained from GeneNetwork (

www.genenetwork.org

). (a) Consumption of 10% ethanol at 2 hours, Spearman’s _r_=−0.82, p=0.02, n=7, GeneNetwork ID 12733 (Cook et al., unpublished). (b) Consumption of 3% ethanol, Spearman’s _r_=−0.82, p=0.02, n=7, GeneNetwork ID 10474 (Phillips et al. 1994). (c) Consumption of 10% ethanol, Spearman’s _r_=−0.82, p=0.02, n=7, GeneNetwork ID 10582 (Rodriguez et al. 1994).

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Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies - PubMed (original) (raw)