Role of acetaldehyde in ethanol-induced elevation of the neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one in rats

Background: Systemic ethanol administration increases neuroactive steroid levels that increase ethanol sensitivity. Acetaldehyde is a biologically active compound that may contribute to behavioral and rewarding effects of ethanol. We investigated the role of acetaldehyde in ethanol‐induced elevations of 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐THP) levels in cerebral cortex. Methods: Male Sprague–Dawley rats were administered ethanol, and plasma acetaldehyde concentrations were measured by gas chromatography to determine relevant concentrations. Rats were then administered acetaldehyde directly, acetaldehyde plus cyanamide to block its degradation, or ethanol in the presence of inhibitors of ethanol metabolism, to determine effects on 3α,5α‐THP levels in cerebral cortex. Results: Ethanol administration (2 g/kg) to rats results in a peak acetaldehyde concentration of 6‐7 μM at 10 minutes that remains stable for the duration of the time points tested. Direct administration of acetaldehyde eliciting this plasma concentration does not increase cerebral cortical 3α,5α‐THP levels, and inhibition of ethanol‐metabolizing enzymes to modify acetaldehyde formation does not alter ethanol‐induced 3α,5α‐THP levels. However, higher doses of acetaldehyde (75 and 100 mg/kg), in the presence of cyanamide to prevent its metabolism, are capable of increasing cortical 3α,5α‐THP levels. Conclusions: Physiological concentrations of acetaldehyde are not responsible for ethanol‐induced increases in 3α,5α‐THP, but a synergistic role for acetaldehyde with ethanol may contribute to increases in 3α,5α‐THP levels and ethanol sensitivity.