Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose☆

Abstract 

Behavioral effects of ethanol are mediated by actions at multiple neurotransmitter receptors and signaling systems; prominent among these is the type A γ-aminobutyric acid (GABA_A) receptor. Previous work has shown that the GABAergic neuroactive steroid allopregnanolone enhances ethanol-reinforced instrumental responding in rat. In the current study, we compared the effects of allopregnanolone with the direct GABA_A agonist muscimol and the direct type B GABA (GABA_B) agonist baclofen in male Long–Evans rats lever pressing for a 10% ethanol solution in a limited-access procedure. The effects of concurrently available sucrose were also tested to determine the selectivity of these drugs for altering ethanol self-administration when an alternate reinforcer was available. In Experiment 1, we found that presession systemic administration of both muscimol (0.3 and 1 mg/kg) and baclofen (1 and 3 mg/kg) reduced responding for ethanol. In contrast, allopregnanolone (3 and 5.6 mg/kg) enhanced responding for ethanol. In Experiment 2, we found that a 1-mg/kg dose of baclofen reduced responding for ethanol, but not for sucrose, whereas both baclofen and muscimol, administered at a higher dose of 3 mg/kg, decreased both ethanol- and sucrose-reinforced responding. Allopregnanolone, at a dose of 5.6 mg/kg, but not of 3 mg/kg, selectively increased ethanol-reinforced responding, indicating a less robust effect of allopregnanolone on responding within the concurrent reinforcement procedure than that observed when ethanol alone was available. The results support the suggestion that direct agonist action at either the GABA_A or the GABA_B receptor decreases ethanol self-administration. Muscimol produces a nonselective decrease in instrumental responding, whereas baclofen may selectively reduce ethanol intake at lower doses, but not higher ones, possibly limiting its potential use for treatment of alcohol abuse in human beings. In contrast, allopregnanolone can selectively enhance ethanol self-administration in the presence of a concurrently available alternate reinforcer, indicating that the direct GABA_A agonist muscimol and the allosteric GABA_A modulator allopregnanolone do not produce similar behavioral effects on instrumental responding for ethanol reinforcement.

Keywords:  Neurosteroid, Allopregnanolone, Muscimol, Baclofen, Operant self-administration, Alcohol