Pharmacological and anatomical evidence for an interaction between mGluR5- and GABAA α1-containing receptors in the discriminative stimulus effects of ethanol
Pharmacological and anatomical evidence for an interaction between mGluR5- and GABAA α1-containing receptors in the discriminative stimulus effects of ethanol
复制标题
DOI：
10.1038/sj.npp.1300616
复制
发表时间：
2005-04-01
影响因子：
7.6
通讯作者：
Hodge, CW
中科院分区：
文献类型：
--
作者：
Besheer, J;Hodge, CW
乙醇的区别性刺激特性部分通过GABA（A）受体的正性调节来介导。最近的证据表明，代谢型谷氨酸受体亚型5（mGluR 5）的活性可以影响GABA（A）受体的功能。因此，这项工作的目的是研究潜在的参与mGluR 5的歧视性刺激效应的乙醇。在训练辨别乙醇（1 g/kg，胃内灌胃（i.g.））的大鼠中，从水中，将2-甲基-6-（苯乙基）-吡啶（MPEP）（1-50 mg/kg，i. p.）mGlu 5受体的选择性非竞争性拮抗剂不产生乙醇样刺激特性。然而，用MPEP（30 mg/kg）预处理降低了乙醇的刺激特性，如乙醇适当响应的显著降低所示，特别是在0.5和1 g/kg乙醇下，并且乙醇测试剂量（1和2 g/kg）未能完全替代乙醇训练剂量。为了测试mGluR 5拮抗作用是否改变乙醇刺激的GABA（A）受体组分，评估了MPEP调节戊巴比妥和地西泮替代乙醇的能力。戊巴比妥替代（1-10 mg/kg，i. p.）乙醇的MPEP预处理没有改变。然而，MPEP预处理抑制地西泮（5 mg/kg，i. p.）的乙醇样刺激特性。为了检查这些药理学发现的潜在解剖学基础，通过双标记荧光免疫组织化学和共聚焦显微镜可视化检查了含mGluR 5和苯二氮卓敏感性GABA（A）α 1受体的表达模式。结果表明，mGluR 5-和GABA（A）α 1-受体都在边缘脑区共表达，并共同定位于特定脑区的相同细胞，包括杏仁核，海马，苍白球，腹侧苍白球。总之，这些发现表明mGluR 5和苯二氮卓敏感性GABA（A）受体在介导乙醇辨别中的相互作用。
The discriminative stimulus properties of ethanol are mediated in part by positive modulation of GABA(A) receptors. Recent evidence indicates that metabotropic glutamate receptor subtype 5 (mGluR5) activity can influence GABA(A) receptor function. Therefore, the purpose of this work was to examine the potential involvement of mGluR5 in the discriminative stimulus effects of ethanol. In rats trained to discriminate ethanol (1 g/kg, intragastric gavage (i.g.)) from water, 2-methyl-6-(phenylethyl)-pyridine (MPEP) (1-50 mg/kg, i.p.) a selective noncompetitive antagonist of the mGlu5 receptor did not produce ethanol-like stimulus properties. However, pretreatment with MPEP (30 mg/kg) reduced the stimulus properties of ethanol as indicated by significant reductions in ethanol-appropriate responding, specifically at 0.5 and 1 g/kg ethanol, and a failure of ethanol test doses (1 and 2 g/kg) to fully substitute for the ethanol training dose. To test whether mGluR5 antagonism altered the GABA(A) receptor component of the ethanol stimulus, the ability of MPEP to modulate pentobarbital and diazepam substitution for ethanol was assessed. Pentobarbital substitution (1-10 mg/kg, i.p.) for ethanol was not altered by MPEP pretreatment. However, MPEP pretreatment inhibited the ethanol-like stimulus properties of diazepam (5 mg/kg, i.p.). To examine a potential anatomical basis for these pharmacological findings, expression patterns of mGluR5- and benzodiazepine-sensitive GABA(A) alpha 1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5- and GABA(A) alpha 1-containing receptors were both coexpressed in limbic brain regions and colocalized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus, and ventral pallidum. Together, these findings suggest an interaction between mGluR5- and benzodiazepine-sensitive GABA(A) receptors in mediating ethanol discrimination.