Besheer Joyce, Hodge Clyde W
Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Neuropsychopharmacology. 2005 Apr;30(4):747-57. doi: 10.1038/sj.npp.1300616.
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) alpha1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5- and GABA(A) alpha1-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.
乙醇的辨别性刺激特性部分是由GABA(A)受体的正向调节介导的。最近的证据表明，代谢型谷氨酸受体5（mGluR5）的活性可以影响GABA(A)受体的功能。因此，本研究的目的是探讨mGluR5在乙醇辨别性刺激效应中的潜在作用。在训练大鼠通过胃内灌胃（i.g.）辨别乙醇（1 g/kg）和水的实验中，mGlu5受体的选择性非竞争性拮抗剂2-甲基-6-（苯乙基）吡啶（MPEP）（1-50 mg/kg，腹腔注射（i.p.））未产生类似乙醇的刺激特性。然而，用MPEP（30 mg/kg）预处理可降低乙醇的刺激特性，表现为乙醇适应性反应显著减少，特别是在0.5和1 g/kg乙醇剂量时，并且乙醇测试剂量（1和2 g/kg）不能完全替代乙醇训练剂量。为了测试mGluR5拮抗作用是否改变了乙醇刺激的GABA(A)受体成分，评估了MPEP调节戊巴比妥和地西泮替代乙醇的能力。MPEP预处理未改变戊巴比妥（1-10 mg/kg，腹腔注射）替代乙醇的情况。然而，MPEP预处理抑制了地西泮（5 mg/kg，腹腔注射）类似乙醇的刺激特性。为了研究这些药理学发现的潜在解剖学基础，通过双标荧光免疫组织化学和共聚焦显微镜观察，检测了mGluR5和对苯二氮䓬敏感的含GABA(A)α1受体的表达模式。结果表明，含mGluR5和GABA(A)α1的受体在边缘脑区共表达，并在包括杏仁核、海马体、苍白球和腹侧苍白球在内的特定脑区的同一细胞上共定位。总之，这些发现表明mGluR5和对苯二氮䓬敏感的GABA(A)受体在介导乙醇辨别过程中存在相互作用。
