Cowen Michael S, Djouma Elvan, Lawrence Andrew J
Howard Florey Institute, Royal Parade, University of Melbourne, Victoria, Australia.
J Pharmacol Exp Ther. 2005 Nov;315(2):590-600. doi: 10.1124/jpet.105.090449. Epub 2005 Jul 13.
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.
代谢型谷氨酸5受体（mGlu5）已被认为在疼痛调节、焦虑、抑郁以及觅药行为中发挥作用。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）对两种品系大鼠（小鹿斑鼠（FH）和近交系嗜酒（iP）大鼠）操作性乙醇自我给药的影响。MTEP（腹腔注射2 mg/kg）使两种品系大鼠对乙醇的反应显著降低；然而，在iP大鼠中，该剂量的MTEP也会引起明显的镇静作用，尽管在较低剂量时仍能降低对酒精的反应。慢性给予MTEP（2 mg/kg/天）在双瓶偏好试验中使FH大鼠的乙醇消耗量显著降低；然而，该剂量的慢性治疗对FH大鼠的焦虑样行为或抑郁样行为没有影响，这表明所用剂量低于抗焦虑或抗抑郁样效应的阈值。最后，重复给予MTEP（腹腔注射2 mg/kg）导致扣带回皮质中编码N-甲基-D-天冬氨酸受体NR1亚基和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体GluR2亚基的mRNA表达显著降低。梨状皮质中NR1表达也显著下降。慢性给予MTEP还导致嗅结节内mGlu5基因表达显著降低，多巴胺转运体和多巴胺D2样受体结合显著增加。总体而言，这些数据表明MTEP可以减少不同酒精中毒啮齿动物模型中的觅酒行为，并且这种作用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。
