Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens.
Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens.
复制标题
DOI：
10.1523/jneurosci.2366-09.2009
复制
发表时间：
2009-07-29
期刊：
影响因子：
--
通讯作者：
Hodge CW
中科院分区：
文献类型：
--
作者：
Besheer J;Grondin JJ;Salling MC;Spanos M;Stevenson RA;Hodge CW
酒精的内感受性效应是成瘾倾向的主要决定因素。代谢型谷氨酸（mGlu）受体广泛表达于纹状体回路中，已知可调节药物寻求。鉴于药物的内感受性效应可能是滥用倾向的重要决定因素，我们假设纹状体mGlu受体调节酒精的内感受性效应。使用药物辨别学习，训练大鼠辨别酒精（lg/kg，i.g.）与水的对抗。我们发现代谢型谷氨酸5型（mGlu 5）受体[10 mg/kg 2-甲基-6-（苯乙炔基）吡啶（MPEP）和3 mg/kg 3-（（2-甲基-1，3-噻唑-4-基）乙炔基）吡啶]，但不是mGlu 1受体（[0.3-3 mg/kg JNJ 16259685）（3，4-二氢-2H-吡喃并[2，3] β-喹啉-7-基）（顺式-4-甲氧基环己基）甲酮）]，抑制乙醇的辨别刺激效应。此外，mGlu 5受体或拮抗剂（10毫克/公斤MPEP）显着抑制神经元的活动，在脑桥核核心的转录因子c-Fos的水平显着降低。因此，靶向抑制延髓核芯中的mGlu 5受体（20 μg MPEP）减弱了酒精（1 g/kg）的辨别刺激效应。通过背内侧尾壳核中缺乏mGlu 5受体（10-30 μg MPEP）的抑制作用以及脑区域之间mGlu 5受体的相似细胞学表达模式和相对密度证实了解剖学特异性。由于mGlu 5受体的激活[10 μg（RS）-2-氨基-2-（2-氯-5-羟基苯基）乙酸钠盐]增强了低酒精剂量（0.5 g/kg）的辨别刺激效应，并且mGlu 5受体抑制（20 μg MPEP）阻止了激动剂诱导的增强，因此证实了内谷氨酰胺mGlu 5受体的功能参与。这些结果表明，mGlu 5受体的活性在脑桥核所需的表达的内感受性效应的酒精。
The interoceptive effects of alcohol are major determinants of addiction liability. Metabotropic glutamate (mGlu) receptors are widely expressed in striatal circuits known to modulate drug-seeking. Given that the interoceptive effects of drugs can be important determinants of abuse liability, we hypothesized that striatal mGlu receptors modulate the interoceptive effects of alcohol. Using drug discrimination learning, rats were trained to discriminate alcohol (1 g/kg, i.g.) versus water. We found that systemic antagonism of metabotropic glutamate subtype 5 (mGlu5) receptors [10 mg/kg 2-methyl-6-(phenylethynyl) pyridine (MPEP) and 3 mg/kg 3-((2-methyl-1,3-thiazol-4-yl)ethynyl) pyridine], but not mGlu1 receptors ([0.3–3 mg/kg JNJ16259685) (3,4-dihydro-2H-pyrano[2,3] β-quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone)], inhibited the discriminative stimulus effects of alcohol. Furthermore, mGlu5 recept or antagonism (10 mg/kg MPEP) significantly inhibited neuronal activity in the nucleus accumbens core as levels of the transcription factor c-Fos were significantly reduced. Accordingly, targeted inhibition of mGlu5 receptors (20 μg of MPEP) in the nucleus accumbens core blunted the discriminative stimulus effects of alcohol (1 g/kg). Anatomical specificity was confirmed by the lack of effect of inhibition of mGlu5 receptors (10–30 μg of MPEP) in the dorsomedial caudate–putamen and the similar cytological expression patterns and relative density of mGlu5 receptors between the brain regions. Functional involvement of intra-accumbens mGlu5 receptors was confirmed as activation of mGlu5 receptors [10 μg of (RS)-2-amino-2-(2-chloro-5-hydroxyphenyl) acetic acid sodium salt] enhanced the discriminative stimulus effects of a low alcohol dose (0.5 g/kg), and mGlu5 receptor inhibition (20 μg of MPEP) prevented the agonist-induced enhancement. These results show that mGlu5 receptor activity in the nucleus accumbens is required for the expression of the interoceptive effects of alcohol.