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 GABAA 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.