Positive allosteric modulators of the GABA A receptor: differential interaction of benzodiazepines and neuroactive steroids with ethanol

Abstract

Endogenous pregnane steroids, such as allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one; 3alpha, 5alpha-P) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one; 3alpha,5beta-P), allosterically modulate GABA(A) receptor function and exhibit behavioral effects similar to benzodiazepines, though acting at a distinct recognition site. Inasmuch as some positive allosteric modulators of GABA(A) receptor function exhibit profound interactions with ethanol, the effects of 3alpha,5alpha-P and 3alpha,5beta-P were compared to those of two benzodiazepines, triazolam and diazepam, on the motor function of mice and rats when administered either alone or in combination with ethanol. All four test compounds exhibited dose-related impairment of motor function in the horizontal wire task in mice and the rotorod task in rats. Ethanol caused a marked enhancement of triazolamand diazepam-induced motor impairment. In contrast, ethanol enhanced to a lesser extent the motor impairment induced by both neurosteroids in mice and not at all in rats. All four compounds increased ethanol-induced behavioral sleep time in mice, although the benzodiazepines did so at a much smaller fraction of their ataxic doses as compared to the neurosteroids. As one of the undesired side-effects of therapeutic use of benzodiazepines is their interaction with ethanol, development of neuroactive steroids as drugs may offer therapeutic advantages.

Altered Postural Control during the Luteal Phase in Women with Premenstrual Symptoms

“…In humans, a high dose of pregnanolone is hypnotic and anesthetic [1, 26]. In parallel with inducing sedation, allopregnanolone has also been shown to induce disturbances in motor function [27, 28]. Long-term treatment with allopregnanolone has been reported to have anxiolytic effects in animals [29], while short-term treatment has been reported to induce anxiety [30].…”

Quantitative Analyses of Antagonism: Combinations of Midazolam and Either Flunitrazepam or Pregnanolone in Rhesus Monkeys Discriminating Midazolam

“…Although benzodiazepines and neuroactive steroids act at distinct sites on GABA A receptors, they both facilitate the actions of GABA, thereby increasing Cl Ϫ flux and producing similar behavioral effects. Like benzodiazepines, neuroactive steroids have anxiolytic (Wieland et al, 1997), sedative (Lancel, 1999;Vanover et al, 1999), and anticonvulsant effects (Kokate et al, 1994;Gasior et al, 2000;Reddy and Rogawski, 2001) and can reverse ethanol withdrawal (Finn et al, 2000). Despite these similarities, the effects of neuroactive steroids and benzodiazepines are not identical, with differences emerging during long-term treatment; for example, tolerance and dependence are less likely to develop during long-term treatment with neuroactive steroids than with benzodiazepines (Kokate et al, 1998;Reddy and Rogawski, 2000;Eppolito and Gerak, 2010).…”

Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol

“…The positive modulators of GABA-A receptor (allopregnanolone and pregnenolone) increased the sleep time and motor loss induced by ethanol in mice. [44][45] Therefore, ethanol and some neurosteroids might have similar effects associated with the GABA-A receptor complex, which may explain the interactions between these drugs. The chronic administration of ethanol has been correlated with a decrease in GABA-A receptor-mediated response sensitivity in the central nervous system.…”