Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Alcohol Clin Exp Res (Hoboken). 2023 Mar;47(3):459-469. doi: 10.1111/acer.15008. Epub 2023 Feb 21.
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 GABA 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.
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.
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.
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.
酒精会影响大脑中的多个回路，主要是扰乱与奖赏回路相关的脑区中抑制性γ-氨基丁酸（GABA）传递和兴奋性谷氨酸信号之间的微妙平衡。这些脑区包括杏仁核、伏隔核（Acb）和腹侧被盖区（VTA）。这种作用会损害调节对酒瘾和觅酒行为的控制的回路。酒精使用障碍（AUD）患者的啮齿动物模型和死后人脑研究都强调了 GABA 能抑制的丧失与成瘾的发展之间的关联。神经甾体（3α,5α）-3-羟基孕烷-20-酮（3α,5α-THP）是 GABA 受体的有效正调节剂。慢性酒精消耗会降低 3α,5α-THP 水平，导致 GABA 抑制减少。我们之前的研究表明，通过过表达胆固醇侧链裂解酶 P450scc 增强神经甾体生物合成，可减少雄性酒精偏好大鼠（P 大鼠）的酒精摄入量。虽然大多数关于酒精诱导改变的证据来自男性受试者的研究，但一些数据表明女性比男性更容易受到酒精的影响。
在这项研究中，我们研究了将 3α,5α-THP 直接输注到两个有助于酒精强化的脑区，即 VTA 和伏隔核核心（AcbC），对雌性 P 大鼠的酒精自我给药的调节能力。
3α,5α-THP 输注到 AcbC 增加了该区域的 3α,5α-THP 阳性细胞表达，并减少了酒精自我给药。相比之下，3α,5α-THP 输注到 VTA 对酒精自我给药没有显著影响，尽管发现有减少的趋势。
我们的结果表明，AcbC 中 3α,5α-THP 的局部增加可能会改变中边缘系统的活动，从而减少酒精的自我给药。
