Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference
Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference
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DOI：
10.1038/sj.npp.1301034
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发表时间：
2007-01-01
影响因子：
7.6
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
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作者：
Hansson, Anita C.;Bermudez-Silvaz, Francisco J.;Heilig, Markus
内源性大麻素信号最近被认为与寻求酒精的行为有关。我们分析了内源性大麻素相关基因在奖励和依赖关键脑区的表达，并比较了偏好酒精的AA （Alko Alcohol）和非偏好酒精的ANA （Alko Non-Alcohol）大鼠系的表达。AA大鼠前额皮质（PFC）主要内源性大麻素降解酶脂肪酸氨基水解酶（FAAH）表达降低，且该区域酶活性降低。内源性大麻素-大麻素1 （CB1）受体配体的结合(3)[H]SR141716A，以及CB1激动剂WIN 55,2 12-2刺激的GTP γ S结合[35S]在同一区域下调。综上所述，这表明AA动物PFC中的内源性大麻素传递过度活跃，CB1信号的代偿性下调。FAAH功能受损对酒精自我给药的功能作用通过两种独立的方式得到验证。CB1拮抗剂SR141716A在AA大鼠全身或局部给予PFC时，有效且剂量依赖性地抑制自我给药，但在纹状体中不起作用。相反，pfc内注射竞争性FAAH抑制剂URB597增加了非选择Wistar大鼠的乙醇自我给药。这些结果首次表明，FAAH功能受损可能导致自发性高酒精摄入量的表型，并指出FAAH既是潜在的易感性因素，也是治疗靶点。
Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoid-related genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand (3)[H]SR141716A, and [35S]GTP gamma S incorporation stimulated by the CB1 agonist WIN 55,2 12-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.