期刊
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
卷 38, 期 7, 页码 1894-1901出版社
WILEY-BLACKWELL
DOI: 10.1111/acer.12414
关键词
5-Hydroxytryptamine; Serotonin; Human; Postmortem; Raphe; Family History
资金
- NIAAA NIH HHS [R01 AA011293, AA11293, R01 AA009004] Funding Source: Medline
- NIMH NIH HHS [R01 MH064168, P50 MH062185, MH62185, MH64168, MH40210, R01 MH040210] Funding Source: Medline
Background: Chronic alcohol use depletes brain serotonin (5-hydroxytryptamine [5-HT]), yet we previously found more tryptophan hydroxylase 2 (TPH2), the rate-limiting biosynthetic enzyme for 5-HT, in the dorsal raphe nucleus (DRN) of alcoholics. We sought to determine whether the increase in amount of TPH2 enzyme is associated with more TPH2 mRNA gene expression in the DRN of a new cohort of alcoholics and controls. Methods: TPH2 mRNA and protein were measured by in situ hybridization and immunoautoradiography, respectively, in the DRN and median raphe nucleus (MRN) of age-and sex-matched pairs (n = 16) of alcoholics and nonpsychiatric controls. Alcohol use disorder diagnosis and medical, psychiatric, and family histories were obtained by psychological autopsy. Age and sex were covariates in the analyses. Results: TPH2 mRNA in alcoholics was greater in the DRN and MRN compared to controls (DRN: controls: 3.6 +/- 1.6, alcoholics: 4.8 +/- 1.8 nCi/mg of tissue, F = 4.106, p = 0.02; MRN: controls: 2.6 +/- 1.2, alcoholics: 3.5 +/- 1.1 nCi/mg of tissue, F = 3.96, p = 0.024). The difference in TPH2 mRNA was present in all DRN subnuclei (dorsal [DRd]: 135%, interfascicular [DRif]: 139%, ventral [DRv]: 135%, ventrolateral [DRvl]: 136% of control p < 0.05) except the caudal subnucleus. Alcoholics also had more TPH2 protein in the DRN and MRN than controls (DRN: controls: 265 +/- 47, alcoholics: 318 +/- 47 mu Ci/g, F = 8.72, p = 0.001; MRN: controls: 250 +/- 33, alcoholics: 345 +/- 39 mu Ci/g, F = 7.78, p = 0.001). There is a positive correlation between TPH2 protein and mRNA expression in the DRN (r = 0.815, p < 0.001), suggesting that the higher amount of TPH2 protein is due to an increase in TPH2 gene expression. Conclusions: These findings suggest that greater TPH2 gene expression is the basis for more TPH2 protein in the DRN and MRN in alcoholics.
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