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Abstract
Alcohol (ethanol, EtOH) withdrawal drives relapse, yet mechanisms remain unclear. Because neuroactive steroids (NAS) positively modulate GABAA_AA receptors, we tested whether endogenous GABAergic NAS buffer acute withdrawal. Male and female DBA/2J and C57BL/6J mice underwent adrenalectomy and/or gonadectomy (ADX, GDX, ADX/GDX) to remove peripheral NAS sources; withdrawal was indexed by handling‑induced convulsions after 4 g/kg EtOH. ADX or ADX/GDX increased withdrawal severity in male DBA/2J and C57BL/6J and in female DBA/2J, but not in female C57BL/6J, implicating progesterone or deoxycorticosterone (not testosterone‑derived NAS). In DBA/2J mice, replacement with progesterone or deoxycorticosterone normalized withdrawal, an effect blocked by 5α‑reductase inhibition (finasteride). Hippocampal qRT‑PCR showed reduced GABAA_AA α1 subunit (and reduced StAR in females) in groups lacking NAS protection. These findings indicate endogenous GABAergic NAS mitigate acute EtOH withdrawal and suggest steroidogenesis and GABAA_AA subunit expression as therapeutic targets.