Lominac Kevin D, Kapasova Zuzana, Hannun Reem A, Patterson Cole, Middaugh Lawrence D, Szumlinski Karen K
Department of Psychology, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA.
Drug Alcohol Depend. 2006 Nov 8;85(2):142-56. doi: 10.1016/j.drugalcdep.2006.04.003. Epub 2006 May 11.
Blockade of the mGluR5 subtype of Group 1 metabotropic glutamate receptor (mGluRs) reduces the rewarding effects of ethanol (EtOH), while the effects of mGluR1a blockade remain under-investigated. The present study compared the effects of pretreatment with the mGluR5 antagonist MPEP and the mGluR1a antagonist CPCCPOEt upon behavioral and neurochemical variables associated with EtOH reward in alcohol-preferring C57BL/6J mice. Pretreatment with either antagonist (0-10 mg/kg, IP) dose-dependently reduced measures of EtOH reward in an operant self-administration paradigm and the maximally effective antagonist dose (10 mg/kg) also blocked the expression of EtOH-induced place conditioning, as well as EtOH consumption under 24-h free-access conditions. MPEP pretreatment did not significantly alter the EtOH dose-locomotor response function; however, it prevented EtOH-induced changes in extracellular dopamine, glutamate and GABA in the nucleus accumbens (NAC). In contrast, CPCCOEt shifted the EtOH dose-response function downwards, enhanced the capacity of higher EtOH doses to elevate NAC levels of GABA and lowered extracellular dopamine and glutamate below baseline following EtOH injection. It is suggested that the "anti-alcohol" effects of MPEP may involve an attenuation of the neurochemical signals mediating EtOH reward, whereas those of CPCCOEt may involve an increased sensitivity to the inhibitory effects of EtOH upon brain and behavior.
阻断第1组代谢型谷氨酸受体（mGluRs）的mGluR5亚型可降低乙醇（EtOH）的奖赏效应，而mGluR1a阻断的效应仍未得到充分研究。本研究比较了用mGluR5拮抗剂MPEP和mGluR1a拮抗剂CPCCOEt预处理对与酒精偏好性C57BL/6J小鼠EtOH奖赏相关的行为和神经化学变量的影响。用任何一种拮抗剂（0 - 10 mg/kg，腹腔注射）预处理均可在操作性自我给药范式中剂量依赖性地降低EtOH奖赏指标，最大有效拮抗剂剂量（10 mg/kg）还可阻断EtOH诱导的位置偏爱表达以及24小时自由摄取条件下的EtOH消耗。MPEP预处理并未显著改变EtOH剂量 - 运动反应函数；然而，它可防止EtOH诱导的伏隔核（NAC）细胞外多巴胺、谷氨酸和GABA的变化。相比之下，CPCCOEt使EtOH剂量反应函数向下移动，增强了较高EtOH剂量升高NAC中GABA水平的能力，并在注射EtOH后使细胞外多巴胺和谷氨酸低于基线水平。提示MPEP的“抗酒精”效应可能涉及介导EtOH奖赏的神经化学信号的减弱，而CPCCOEt的效应可能涉及对EtOH对大脑和行为抑制作用的敏感性增加。
