Department of Psychiatry, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, 27599, USA.
Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, 27599, USA.
Neuropharmacology. 2021 Mar 15;186:108463. doi: 10.1016/j.neuropharm.2021.108463. Epub 2021 Jan 16.
CRF is the main activator of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. CRF neurons are found mainly in the hypothalamus, but CRF positive cells and CRF1 receptors are also found in extrahypothalamic structures, including amygdala (CeA), hippocampus, NAc and VTA. CRF release in the hypothalamus is regulated by inhibitory GABAergic interneurons and extrahypothalamic glutamatergic inputs, and disruption of this balance is found in stress-related disorders and addiction. (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP), the most potent positive modulator of GABA receptors, attenuates the stress response reducing hypothalamic CRF mRNA expression and ACTH and corticosterone serum levels. In this study, we explored 3α,5α-THP regulation of hypothalamic and extrahypothalamic CRF mRNA and peptide expression, in male and female Sprague Dawley rats, following vehicle or 3α,5α-THP administration (15 mg/kg). In the hypothalamus, we found sex differences in CRF mRNA expression (females +74%, p < 0.01) and CRF peptide levels (females -71%, p < 0.001). 3α,5α-THP administration reduced hypothalamic CRF mRNA expression only in males (-50%, p < 0.05) and did not alter CRF peptide expression in either sex. In hippocampus and CeA, 3α,5α-THP administration reduced CRF peptide concentrations only in the male (hippocampus -29%, p < 0.05; CeA -62%, p < 0.01). In contrast, 3α,5α-THP injection increased CRF peptide concentration in the VTA of both males (+32%, p < 0.01) and females (+26%, p < 0.01). The results show sex and region-specific regulation of CRF signals and the response to 3α,5α-THP administration. This data may be key to successful development of therapeutic approaches for stress-related disorders and addiction.
CRF 是下丘脑-垂体-肾上腺 (HPA) 轴对压力作出反应的主要激活物。CRF 神经元主要存在于下丘脑，但在神经内分泌外的结构中也发现了 CRF 阳性细胞和 CRF1 受体，包括杏仁核 (CeA)、海马体、伏隔核和 VTA。下丘脑 CRF 的释放受到抑制性 GABA 能中间神经元和神经内分泌外谷氨酸能传入的调节，而这种平衡的破坏在应激相关障碍和成瘾中被发现。(3α,5α)3-羟基孕烷-20-酮 (3α,5α-THP) 是 GABA 受体最强的正变构调节剂，可减轻应激反应，降低下丘脑 CRF mRNA 表达和 ACTH 和皮质酮血清水平。在这项研究中，我们探索了 3α,5α-THP 对雄性和雌性 Sprague Dawley 大鼠下丘脑和神经内分泌外 CRF mRNA 和肽表达的调节作用，在给予载体或 3α,5α-THP 给药 (15mg/kg) 后。在下丘脑，我们发现 CRF mRNA 表达存在性别差异 (女性 +74%，p<0.01) 和 CRF 肽水平 (女性 -71%，p<0.001)。3α,5α-THP 给药仅减少雄性下丘脑 CRF mRNA 表达 (-50%，p<0.05)，而不改变两性的 CRF 肽表达。在海马体和 CeA 中，3α,5α-THP 给药仅减少雄性的 CRF 肽浓度 (-29%，p<0.05；CeA -62%，p<0.01)。相比之下，3α,5α-THP 注射增加了两性 VTA 中的 CRF 肽浓度 (+32%，p<0.01) 和女性 (+26%，p<0.01)。结果表明，CRF 信号的性别和区域特异性调节以及对 3α,5α-THP 给药的反应。这些数据可能是开发应激相关障碍和成瘾治疗方法的关键。
