Centre for Neuroscience, Division of Medical Sciences, University of Dundee Medical School, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
Behav Brain Res. 2011 Jun 1;219(2):354-7. doi: 10.1016/j.bbr.2010.12.024. Epub 2011 Jan 7.
Previous studies have shown that the prior administration of metabotropic glutamate receptor 5 (MGluR5) receptor antagonists inhibit responding for nicotine in an intravenous self-administration experiment. However, recent studies in this laboratory have shown that an mGluR5 receptor antagonist, MPEP (2-methyl-6-(phenylethynyl)-pyridine), also attenuates contextually-conditioned responding evoked by cues associated with the delivery or availability of nicotine. Thus, the results to date do not provide unequivocal evidence that the effects of mGluR5 receptor antagonists on responding for nicotine reflect a direct functional interaction between the antagonists and nicotine per se. This study employed in vivo microdialysis to test the hypothesis that the prior administration of the mGluR5 receptor antagonist, MPEP, inhibits a neural response to nicotine, increased dopamine (DA) overflow in the nucleus accumbens, implicated in directly in nicotine reinforcement. The results confirmed that prior administration of MPEP (2.5 mg/kg and 5 mg/kg IP) dose-dependently reduced responding for nicotine in a self-administration experiment. The higher dose caused complete inhibition of responding in a majority of the animals tested. MPEP injections, over the same dose range, also inhibited the effects of nicotine on DA overflow in the shell and core subdivisions of the rat nucleus accumbens. It is concluded that the data support the hypothesis that, in addition to their putative role in contextually-conditioned responding for nicotine, mGluR5 receptors are also implicated the primary reinforcing properties of the drug which depend upon increased DA overflow in the nucleus accumbens.
先前的研究表明，代谢型谷氨酸受体 5（mGluR5）受体拮抗剂的预先给药可抑制静脉内自我给药实验中尼古丁的反应。然而，本实验室最近的研究表明，mGluR5 受体拮抗剂 MPEP（2-甲基-6-（苯乙炔基）-吡啶）也可减轻与尼古丁的给予或可获得相关的线索引起的条件性反应。因此，迄今为止的结果并未提供明确的证据表明 mGluR5 受体拮抗剂对尼古丁反应的影响反映了拮抗剂与尼古丁本身之间的直接功能相互作用。本研究采用体内微透析来检验以下假设：mGluR5 受体拮抗剂 MPEP 的预先给药可抑制对尼古丁的神经反应，增加伏隔核中的多巴胺（DA）溢出，这与尼古丁的直接强化作用直接相关。结果证实，MPEP（2.5mg/kg 和 5mg/kg IP）的预先给药可剂量依赖性地减少自我给药实验中对尼古丁的反应。较高的剂量导致大多数接受测试的动物的反应完全抑制。在相同的剂量范围内，MPEP 注射也抑制了尼古丁对大鼠伏隔核壳和核心亚区 DA 溢出的影响。结论是，这些数据支持以下假设，即除了它们在与尼古丁相关的条件性反应中的假定作用外，mGluR5 受体还与药物的主要强化特性有关，这取决于伏隔核中 DA 溢出的增加。
