The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems
The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems
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DOI：
10.1124/jpet.105.090449
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Lawrence, AJ
中科院分区：
文献类型：
--
作者：
Cowen, MS;Djouma, E;Lawrence, AJ
代谢型谷氨酸5受体（mGlu5）被认为在疼痛调节、焦虑、抑郁以及觅药行为中起作用。在本研究中，我们检测了选择性mGlu5受体拮抗剂3 - [（2 - 甲基 - 1,3 - 噻唑 - 4 - 基）乙炔基] - 吡啶（MTEP）对两种大鼠品系——弗恩 - 胡德（FH）大鼠和近交系嗜酒（iP）大鼠操作性乙醇自我给药的影响。MTEP（2mg/kg腹腔注射）使两种品系的大鼠对乙醇的反应显著降低；然而，在iP大鼠中，此剂量的MTEP还引起了明显的镇静作用，尽管在较低剂量时仍能降低对酒精的反应。在双瓶偏好实验中，慢性MTEP（2mg/kg/天）使FH大鼠的乙醇摄入量显著减少；然而，此剂量的慢性治疗对FH大鼠的焦虑样行为或抑郁样行为没有影响，这表明所使用的剂量低于产生抗焦虑或抗抑郁样作用的阈值。最后，重复给予MTEP（2mg/kg腹腔注射）使扣带皮层中编码N - 甲基 - D - 天冬氨酸受体的NR1亚基和α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸受体的GluR2亚基的mRNA表达显著降低。梨状皮层中NR1的表达也显著降低。慢性MTEP还使嗅结节内mGlu5基因表达显著降低，多巴胺转运体和多巴胺D - 2样受体结合显著增加。总体而言，这些数据表明MTEP可以减少不同酒精成瘾啮齿动物模型中的觅酒行为，并且这种效应与皮质谷氨酸系统的调节有关，特别是与嗅觉相关区域的调节有关。
The metabotropic glutamate 5 receptor (mGlu5) receptor has been implicated as having a role in pain modulation, anxiety, and depression, as well as drug-seeking behavior. In the present study, we examined the effect of the selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on operant ethanol self-administration by two strains of rats, the Fawn-Hooded (FH) rat and the inbred alcohol-preferring (iP) rat. MTEP (2 mg/kg i.p.) caused a significant reduction in responding for ethanol by both strains of rats; however, in the iP rats, MTEP also induced apparent sedation at this dose, although still reduced alcohol responding at lower doses. Chronic MTEP (2 mg/kg/day) caused a significant reduction in ethanol consumption by FH rats in a two-bottle preference test; however, chronic treatment with this dose had no effect on anxiety-like behavior or depressive-like behavior in FH rats, suggesting the dose used was subthreshold for anxiolytic or antidepressive-like effects. Finally, repeated dosing with MTEP (2 mg/kg i.p.) caused significant reductions in expression of the mRNA encoding the NR1 subunit of the N-methyl-D- aspartate receptor and the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor in the cingulate cortex. A significant decrease in NR1 expression also occurred in the piriform cortex. Chronic MTEP also caused a significant decrease in mGlu5 gene expression and a significant increase in dopamine transporter and dopamine D-2-like receptor binding within the olfactory tubercle. Collectively, these data suggest that MTEP can reduce alcohol-seeking behavior in different rodent models of alcoholism, and this effect is associated with regulation of cortical glutamate systems, particularly those in olfactory-related regions.