Catalase is the key enzyme of ethanol oxidation in the brain of rodents: it may be responsible for about 60% of the process. CYP2E1 plays an important role in ethanol oxidation in the rodent brains. Alcohol dehydrogenase plays a minor role, if any, in this process. Aldehyde dehydrogenase plays the crucial role in the further oxidation of ethanol-derived AC in the brain homogenates.

Major depression represents a complex mental disorder. The identification of biological markers that define subtypes of major depressive disorder would greatly facilitate appropriate medical treatments, as well as provide insight into etiology. Reduced activity of the cAMP signaling system has been implicated in the etiology of major depression. Previous work has shown low adenylyl cyclase activity in platelets and postmortem brain tissue of depressed individuals. Here, we investigate the role of the brain type VII isoform of adenylyl cyclase (AC7) in the manifestation of depressive symptoms in genetically modified animals, using a combination of in vivo behavioral experiments, gene expression profiling, and bioinformatics. We also completed studies with humans on the association of polymorphisms in the AC7 gene with major depressive illness (unipolar depression) based on Diagnostic and Statistical Manual of Mental Disorders IV criteria. Collectively, our results demonstrate a sex-specific influence of the AC7 gene on a heritable form of depressive illness.

Although ethanol has been considered to be an anxiolytic agent, consumption of ethanol has also been shown to increase plasma adrenocorticotropin and glucocorticoids. The corticotrophin-releasing factor (CRF) receptor 1␣ (CRF-R1) is a G protein-coupled receptor that activates adenylyl cyclase (AC), leading to adrenocorticotropin (and subsequently glucocorticoid) release into the circulation. There are nine members of the membrane-bound AC family, and the type 7 AC (AC7) is most sensitive to ethanol, which enhances the responsiveness of AC7 to G protein-coupled receptor activation. We determined the time course of ethanol's effect on plasma adrenocorticotropin and corticosterone levels in male and female AC7 transgenic (Adcy7 huTG ) mice (in which AC7 is overexpressed in neural tissue) and AC7 heterozygous knockdown [Adcy7(ϩ/Ϫ)] mice (in which AC7 is underexpressed in neural tissue), and their respective littermate controls [wild type (WT)]. CRF-R1 mRNA and mRNA and protein for different forms of ACs were measured by using gene expression arrays, quantitative reverse transcription-polymerase chain reaction, and immunoblotting in pituitaries of all animals. Our results demonstrated increased levels of AC7 in pituitary of Adcy7 huTG mice and decreased levels in pituitary of Adcy7(ϩ/Ϫ) mice compared with WT animals. Male and female Adcy7 huTG mice displayed higher plasma adrenocorticotropin and corticosterone levels than WT and/or Adcy7(ϩ/Ϫ) mice after ethanol injection. Female mice displayed higher adrenocorticotropin and corticosterone levels after ethanol injection than males, regardless of genotype. The data provide evidence for an integral role of AC7 in the increase of plasma adrenocorticotropin and corticosterone levels during alcohol intoxication.

BackgroundAlcohol has been shown to critically modulate cyclic adenosine-3′,5′ monophosphate (cAMP) signaling. A number of downstream effectors that respond to the cAMP signals (e.g., protein kinase A, cAMP response element binding protein) have, in turn, been examined in relation to alcohol consumption. These studies did not, however, delineate the point at which the actions of alcohol on the cAMP cascade might translate into differences in drinking behavior. To further understand the role of cAMP synthesis in alcohol drinking and dependence, we investigated a specific adenylyl cyclase isoform, adenylyl cyclase (AC) Type 7, whose activity is selectively enhanced by ethanol.MethodsWe measured alcohol consumption and preference in mice in which one copy of the Adcy7 gene was disrupted (Adcy7+/−). To demonstrate relevance of this gene for alcohol dependence in humans, we tested the association of polymorphisms in the ADCY7 gene with alcohol dependence in a sample of 1703 alcohol-dependent individuals and 1347 control subjects.ResultsWe show that Adcy7+/− female mice have higher preference for alcohol than wild-type mice, whereas there is little difference in alcohol consumption or preference between Adcy7+/− male mice and wild-type control subjects. In the human sample, we found that single nucleotide polymorphisms in ADCY7 associate with alcohol dependence in women, and these markers are also associated with ADCY7 expression (messenger RNA) levels.ConclusionsThese findings implicate adenylyl cyclase Type 7 as a critical component of the molecular pathways contributing to alcohol drinking and the development of alcohol dependence.

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.