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

L. Ornelas,Giorgia Boero,Kalynn J Van Voorhies,T. O’Buckley,J. Besheer,A. Morrow

Published 2023 in Alcoholism: Clinical and Experimental Research

ABSTRACT

BACKGROUND Each year, more than 140,000 deaths occur due to excessive alcohol use. Alcohol affects multiple circuits in the brain, mainly disrupting the delicate balance between inhibitory γ-aminobutyric acid (GABA) transmission and excitatory glutamate signaling in brain areas involved in reward circuits, such as amygdala, nucleus accumbens (Acb) and ventral tegmental area (VTA), causing loss of control in circuits that regulate behavioral control of craving, alcohol-seeking and intake. Many studies have established that alcohol induces alterations in GABAergic transmission and highlighted the association between the loss of GABAergic inhibition with the development of addiction, in both rodent models and post-mortem human brain of patients with alcohol use disorder (AUD). The neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) is a potent positive modulator of GABAA receptors. Chronic alcohol consumption reduces 3α,5α-THP levels, resulting in a decrease of GABA inhibition. We previously demonstrated that enhancing neurosteroid biosynthesis by over-expression of the cholesterol side-chain cleavage enzyme P450scc decreased alcohol intake in male alcohol-preferring rats (P-rats). Most of the evidence of alcohol-induced alterations are conducted in male subjects only, although few data show that females are more vulnerable to alcohol effects than males. METHODS In this study, we investigated the ability of 3α,5α-THP direct infusions in two brain regions contributing to alcohol reinforcement, VTA and Acb core (AcbC), to regulate alcohol self-administration, in female P-rats. RESULTS Administration of 3α,5α-THP into the AcbC increased 3α,5α-THP-positive cells expression in this area and reduced alcohol self-administration. In contrast, 3α,5α-THP infusion into VTA did not significantly affect alcohol self-administration, though trends for a reduction were found. CONCLUSIONS Our results suggest that local increases of 3α,5α-THP into the AcbC may alter mesolimbic activity that drives reduction in alcohol self-administration.

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