Vadasz Csaba, Gyetvai Beatrix M
Laboratory of Neurobehavior Genetics, Nathan S. Kline Institute for Psychiatric Research 140 Old Orangeburg Rd., 10962, Orangeburg, NY, USA.
Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA.
Drug Alcohol Depend Rep. 2021 Dec 12;2:100012. doi: 10.1016/j.dadr.2021.100012. eCollection 2022 Mar.
To test the hypothesis that predisposition to high alcohol drinking behavior is genetically associated with hypoactive serotonergic function in the Nucleus Accumbens (NAc).
Alcohol avoiding C5A3 and alcohol preferring I5B25A mice of the Quasi-congenic Recombinant QTL Introgression (RQI) mouse strains were subjected to in vivo microdialysis in the NAc. Neurotransmitter and metabolite contents were analyzed by HPLC and samples were collected in three phases: Baseline, Control, and Alcohol. Samples were collected with 20 min intervals.
Between-strain differences restricted to small chromosome segments significantly affected both alcohol preference drinking and NAc 5-HIAA levels [F = 5.569 =.035 (General Linear Model Repeated Measures ANOVA and Tests of Between-Subjects Effects)]. Whole genome biallelic DNA marker genotyping allowed the identification of 16 differential microsatellite markers associated with low 5-HIAA levels and excessive alcohol drinking. Chromosome 6 markers were linked to (51.19 centimorgan), a reported candidate gene for modulation of addiction. The results are consistent with earlier reports of association of low 5-HIAA and high alcohol consumption in rats and primates, including Homo sapiens.
Low NAc 5-HIAA and high alcohol consumption are genetically associated in a quasi-congenic mouse model carrying variants of the gene. We propose that constitutional polymorphism in may modulate CRF neuron activity via altered mGluR7 expression thus targeting CRF pathways to substance use circuits. This raises the possibility of modulation of DRN 5-HT neurons leading to hypo- or hyper-serotonergic condition in NAc and higher or lower alcohol preference drinking.
验证伏隔核（NAc）中血清素能功能减退与高酒精饮用行为易感性存在基因关联这一假设。
对近交重组QTL导入（RQI）小鼠品系中避酒精的C5A3和嗜酒精的I5B25A小鼠进行NAc体内微透析。通过高效液相色谱法分析神经递质和代谢物含量，并在三个阶段采集样本：基线期、对照期和酒精期。样本每隔20分钟采集一次。
局限于小染色体片段的品系间差异显著影响酒精偏好性饮用和NAc中5-羟吲哚乙酸（5-HIAA）水平[F = 5.569，P = 0.035（一般线性模型重复测量方差分析和组间效应检验）]。全基因组双等位基因DNA标记基因分型可鉴定出16个与低5-HIAA水平和过度酒精饮用相关的差异微卫星标记。6号染色体标记与（51.19厘摩）相连，这是一个已报道的成瘾调节候选基因。结果与之前关于大鼠和灵长类动物（包括智人）中低5-HIAA与高酒精摄入量关联的报道一致。
在携带该基因变体的近交小鼠模型中，低NAc 5-HIAA与高酒精摄入量存在基因关联。我们提出，该基因的结构多态性可能通过改变代谢型谷氨酸受体7（mGluR7）表达来调节促肾上腺皮质激素释放因子（CRF）神经元活性，从而将CRF通路靶向物质使用回路。这增加了调节中缝背核5-羟色胺（5-HT）神经元导致NAc中血清素能功能减退或亢进以及酒精偏好性饮用增加或减少的可能性。
