(3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) regulation of hypothalamic and extrahypothalamic corticotropin releasing factor (CRF): Sexual dimorphism and brain region specificity in Sprague Dawley rats

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 extra-hypothalamic structures, including amygdala (CeA), hippocampus, NAc and VTA. CRF release in the hypo-thalamus is regulated by inhibitory GABAergic interneurons and extrahypothalamic glutamatergic inputs, and disruption of this balance is found in stress-related disorders and addiction. (3 alpha,5 alpha)3-hydroxypregnan-20-one (3 alpha,5 alpha-THP), the most potent positive modulator of GABAA receptors, attenuates the stress response reducing hypothalamic CRF mRNA expression and ACTH and corticosterone serum levels. In this study, we explored 3 alpha,5 alpha-THP regulation of hypothalamic and extrahypothalamic CRF mRNA and peptide expression, in male and female Sprague Dawley rats, following vehicle or 3 alpha,5 alpha-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). 3 alpha,5 alpha-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, 3 alpha,5 alpha-THP administration reduced CRF peptide concentrations only in the male (hippocampus-29%, p < 0.05; CeA-62%, p < 0.01). In contrast, 3 alpha,5 alpha-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 3 alpha,5 alpha-THP administration. This data may be key to successful development of therapeutic approaches for stress-related disorders and addiction.

Automated summary

CRF is the main activator of the HPA axis in response to stress, with CRF neurons mainly located in the hypothalamus. 3 alpha,5 alpha-THP attenuates the stress response by reducing hypothalamic CRF mRNA expression and serum corticosterone levels. Sex and region-specific regulation of CRF signals in response to 3 alpha,5 alpha-THP administration may be essential for developing therapies for stress-related disorders and addiction.