Pharmacological administration of 3 alpha,5 alpha-THP into the nucleus accumbens core increases 3 alpha,5 alpha-THP expression and reduces alcohol self-administration

BackgroundAlcohol affects multiple circuits in the brain, mainly disrupting the delicate balance between inhibitory gamma-aminobutyric acid (GABA) transmission and excitatory glutamate signaling in brain areas involved in reward circuits. These include the amygdala, nucleus accumbens (Acb), and ventral tegmental area (VTA). This action impairs circuits that regulate behavioral control of craving and alcohol seeking and intake. Studies in both rodent models and postmortem human brain of patients with alcohol use disorder (AUD) have highlighted the association between the loss of GABAergic inhibition and the development of addiction. The neurosteroid (3 alpha,5 alpha)-3-hydroxypregnan-20-one (3 alpha,5 alpha-THP) is a potent positive modulator of GABA(A) receptors. Chronic alcohol consumption reduces 3 alpha,5 alpha-THP levels, resulting in decreased GABA inhibition. We previously demonstrated that enhancing neurosteroid biosynthesis by overexpression of the cholesterol side-chain cleavage enzyme P450scc decreased alcohol intake in male alcohol-preferring rats (P-rats). While most of the evidence of alcohol-induced alterations comes from studies in male subjects, some data show that females are more vulnerable to alcohol's effects than males.MethodsIn this study, we investigated the ability of 3 alpha,5 alpha-THP direct infusions in two brain regions that contribute to alcohol reinforcement, the VTA and Acb core (AcbC), to regulate alcohol self-administration in female P-rats.ResultsAdministration of 3 alpha,5 alpha-THP into the AcbC increased 3 alpha,5 alpha-THP-positive cell expression in this area and reduced alcohol self-administration. By contrast, 3 alpha,5 alpha-THP infusion into the VTA did not significantly affect alcohol self-administration, though trends for a reduction were found.ConclusionsOur results show that local increases in 3 alpha,5 alpha-THP in the AcbC may alter mesolimbic activity that drives a reduction in alcohol self-administration.