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

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)-3hydroxypregnan-20-one (3α,5α-THP) is a potent positive modulator of GABA A 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.

Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats

“…Indeed, the efficacy of 3α,5α-THP administration to reduce cocaine reinstatement was observed in cocaine-dependent animals [ 48 , 49 ], and female rats were more sensitive to this effect [ 50 , 51 ]. Other findings showed that pregnenolone and its GABAergic metabolites regulate alcohol motivation by reducing alcohol seeking and intake in rodents [ 52 , 53 , 54 ]. These results were confirmed in clinical studies in patients with history of cocaine and alcohol use disorders [ 55 , 56 ].…”

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

“…Additionally, studies in alcohol-preferring P rats by O'Dell et al (2005) [395] and Besheer et al (2010) [48] demonstrate that systemic administration of pregnenolone, epiallopregnanolone (3β,5β-THP), or the synthetic neurosteroid 3α,5β-20-oxo-pregnane-3-carboxylic acid (3α,5β-PC) reduces ethanol self-administration. Furthermore, Ornelas et al (2023) [50] found that infusion of allopregnanolone in the nucleus accumbens decreases alcohol self-administration in female P rats.…”