Role of adenylyl cyclase type VII in signaling through CRFR1α receptors and HPA axis activation during ethanol intoxication: study using male and female animals

Abstract

Ethanol (Eth) can increase plasma ACTH and glucocorticoids even though Eth is thought to be anxiolytic. Studies using corticotrophs, have indicated that CRF 1α receptors (CRF‐R1α) initiate ACTH release through coupling to adenylyl cyclase type 9 and type 7 (AC7). Prior studies have shown that Eth enhances AC7 responsiveness to Gsα. We hypothesized that Eth through increasing the affinity of the AC7 for Gsα, can increase CRF‐R1α signaling, leading to increased ACTH levels.We measured plasma ACTH and corticosterone (CS) levels after ip injection of Eth (2.25 g/kg) at time points of 0‐75 min in male and female AC7 transgenic (TG) and heterozygous knockdown (HET) mice. TG mice with transgene (human) AC7 mRNA had significantly higher (≈38%) AC7 protein in the pituitary, as measured with our antibody to AC7. HET mice had ≈50% lower levels of AC7 mRNA and significantly lower (≈26%) pituitary amounts of AC7 protein compared to WT mice.After ip Eth TG male mice displayed significantly higher plasma ACTH levels compared to WT and HET group. The HET group displayed significantly lower ACTH levels in plasma. Over‐ or underexpression of AC7 in brains of mice may be a key factor in differential ACTH response of these animals to alcohol.ACTH and especially CS levels were markedly higher in female mice compared to male mice despite the same blood alcohol levels.Supported by NIAAA and Banbury Foundation.