Pharmacological administration of 3α,5α-THP into the nucleus accumbens core increases 3α,5α-THP expression and reduces alcohol self-administration - PubMed (original) (raw)

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

Laura C Ornelas et al. Alcohol Clin Exp Res (Hoboken). 2023 Mar.

Abstract

Background: 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. 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 (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 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.

Methods: In this study, we investigated the ability of 3α,5α-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.

Results: Administration of 3α,5α-THP into the AcbC increased 3α,5α-THP-positive cell expression in this area and reduced alcohol self-administration. By contrast, 3α,5α-THP infusion into the VTA did not significantly affect alcohol self-administration, though trends for a reduction were found.

Conclusions: Our results show that local increases in 3α,5α-THP in the AcbC may alter mesolimbic activity that drives a reduction in alcohol self-administration.

Keywords: alcohol use disorder; allopregnanolone; nucleus accumbens.

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Figures

Figure 1.

Effects of intra-VTA infusion of 3α,5α-THP on operant alcohol self-administration. Bilateral VTA cannula placements and representative photomicrograph (4X) (A). Infusion of 3α,5α-THP did not alter cumulative alcohol lever responses (B), total alcohol lever responses (g/kg) (C) or locomotor activity (D). Mean ± SEM. * by group labels = main effect of group.

Figure 2.

Effects of intra-AcbC infusion of 3α,5α-THP on operant alcohol self-administration. Bilateral AcbC cannula placements and representative photomicrograph (4X) (A). Infusion of 3α,5α-THP reduced cumulative alcohol lever responses (B). Infusion of 3α,5α-THP (1000 uM) reduced total alcohol lever responses (C). Infusion of 3α,5α-THP did not alter locomotor activity (D). Mean ± SEM. * by group labels = main effect of group.

Figure 3.

Effects of 3α,5α-THP (1000 uM) administration into the AcbC on 3α,5α-THP expression. Terminal intra-AcbC infusion of 3α,5α-THP (1000μM) increased 3α,5α-THP immunoreactivity in the AcbC (A), but not in AcbSh (B). Atlas image depicting the quantified region of interest, AcbC (C). Representative photomicrographs (10x) of cellular 3α,5α-THP immunoreactivity in the AcbC following 3α,5α-THP (1000 μM) infusion in the AcbC (D). Mean ± SEM. * by group labels = main effect of group.

Figure 4.

Schematic representation of brain reward circuitry implicated in addiction. Acb receives dopaminergic (DA, blue) inputs from VTA and substantia nigra (SN), and glutamatergic (glut, green) from medial prefrontal cortex (mPFC), hippocampus (HP), thalamus, and amygdala (AMY). Acb sends GABAergic (GABA, red) efferent projections back to VTA and SN, thalamus, lateral hypothalamus (HYP), amygdala and ventral globus pallidus (vPD).

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Pharmacological administration of 3α,5α-THP into the nucleus accumbens core increases 3α,5α-THP expression and reduces alcohol self-administration - PubMed (original) (raw)