, Volume 180, Issue 2, pp 267-278
Date: 18 Feb 2005

Evaluation of GABAergic neuroactive steroid 3α-hydroxy-5α-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats

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Abstract

Rationale

Acute systemic ethanol administration is known to elevate plasma and cerebral levels of neuroactive steroid 3α-hydroxy-5α-pregnane-20-one (3α, 5α-THP; allopregnanolone) to a concentration sufficient to potentiate GABAA receptors. We have earlier demonstrated that 3α, 5α-THP mediates the antidepressant-like effect of ethanol in Porsolt forced swim test.

Objective

The aim of the present study is to explain the relationship between endogenous GABAergic neurosteroids and anxiolytic effect of ethanol in Sprague–Dawley rats.

Method

The mediation of 3α, 5α-THP in the anti-anxiety effect of ethanol was assessed by pharmacological interactions of ethanol with various endogenous neurosteroidal modulators and using simulated physiological conditions of altered neurosteroid content in elevated plus maze (EPM) test.

Results

Pretreatment of 3α, 5α-THP (0.5–2.5 μg/rat, i.c.v.) or neurosteroidogenic agents such as 3α, 5α-THP precursor progesterone (5 or 10 mg/kg, i.p.), 11-β hydroxylase inhibitor metyrapone (50 or 100 mg/kg, i.p.) or the GABAA receptor agonist muscimol (25 ng/rat, i.c.v.) significantly potentiated the anti-anxiety effect of ethanol (1 g/kg, i.p.). On the other hand, the GABAergic antagonistic neurosteroid dehydroepiandrosterone sulphate (DHEAS) (1 mg/kg, i.p.), the GABAA receptor blocker bicuculline (1 mg/kg, i.p.), the 5α-reductase inhibitor finasteride (50×2 mg/kg, s.c.) or the mitochondrial diazepam binding inhibitory receptor antagonist PK11195 (1 mg/kg, i.p.) reduced ethanol-induced preference of time spent and number of entries into open arms. Anti-anxiety effect of ethanol was abolished in adrenalectomized (ADX) rats as compared to sham-operated control. This ADX-induced blockade was restored by prior systemic injection of progesterone, signifying the contribution of peripheral steroidogenesis in ethanol anxiolysis. Socially isolated animals known to exhibit decreased brain 3α, 5α-THP and GABAA receptor functions displayed reduced sensitivity to the effects of ethanol and 3α, 5α-THP in EPM test.

Conclusions

Our results demonstrated the contributory role of neuroactive steroid 3α, 5α-THP in the anti-anxiety effect of ethanol. It is speculated that ethanol-induced modulation of endogenous GABAergic neurosteroids, especially 3α, 5α-THP, might be crucial pertinent to the etiology of ‘trait’ anxiety (tension reduction) and ethanol abuse.