Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism.
Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: involvement of a ventral pallidal GABAergic mechanism.
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DOI：
10.1038/npp.2008.236
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发表时间：
2009-06
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影响因子：
--
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代谢型谷氨酸受体7（mGluR7）作为治疗癫痫、抑郁症和焦虑症的潜在靶点受到了广泛关注。在这项研究中，我们调查了mGluR7在药物成瘾动物模型中可能参与可卡因奖励。用选择性mGluR7变构激动剂N，N'-二苯甲基-乙烷-1，2-二胺二盐酸盐（AMN082; 1 - 20 mg/kg，i.p.）剂量依赖性地抑制可卡因诱导的增强电脑刺激奖励和静脉内可卡因自我管理下的固定比例和累进比例的强化条件，但未能改变基础或可卡因增强运动或口服蔗糖自我管理，这表明可卡因奖励的特异性抑制。将AMN082（每侧1 - 5 μ g/μ l）微量注射到丘脑腹侧核（NAc）或腹侧苍白球（VP）中，但不注射到背侧纹状体中，也以剂量依赖性方式抑制可卡因自我给药。NAc内或VP内联合给药6-（4-甲氧基苯基）-5-甲基-3-吡啶-4-基异恶唑并[4，5-c]吡啶-4（5H）-酮（MMPIP，每侧5 μ g/μ l）（一种选择性mGluR7变构拮抗剂）可显著阻断AMN 082的作用，表明在这些脑区存在mGluR7介导的效应。体内微透析证明可卡因（10 mg/kg，i.p.）预激显著升高NAc或VP中的细胞外DA，而降低VP中的细胞外GABA（但不影响NAc）。AMN082预处理选择性地阻断可卡因诱导的细胞外GABA的变化，但不是在DA中，在幼稚大鼠和可卡因自我给药大鼠。这些数据表明：（1）mGluR7在可卡因的急性强化中起关键作用;（2）腹侧纹状体苍白通路中的GABA依赖性机制而非DA依赖性机制似乎是AMN082作用的基础;（3）AMN082或其他mGluR7选择性激动剂可用于治疗可卡因成瘾。
The metabotropic glutamate receptor 7 (mGluR7) has received much attention as a potential target for the treatment of epilepsy, major depression, and anxiety. In this study, we investigated the possible involvement of mGluR7 in cocaine reward in animal models of drug addiction. Pretreatment with the selective mGluR7 allosteric agonist N,N’-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082; 1-20 mg/kg, i.p.) dose-dependently inhibited cocaine-induced enhancement of electrical brain-stimulation reward and intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, but failed to alter either basal or cocaine-enhanced locomotion or oral sucrose self-administration, suggesting a specific inhibition of cocaine reward. Microinjections of AMN082 (1–5 μg/μl per side) into the nucleus accumbens (NAc) or ventral pallidum (VP), but not dorsal striatum, also inhibited cocaine self-administration in a dose-dependent manner. Intra-NAc or intra-VP co-administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP, 5 μg/μl per side), a selective mGluR7 allosteric antagonist, significantly blocked AMN082’s action, suggesting an effect mediated by mGluR7 in these brain regions. In vivo microdialysis demonstrated that cocaine (10 mg/kg, i.p.) priming significantly elevated extracellular DA in the NAc or VP, while decreasing extracellular GABA in VP (but not in NAc). AMN082 pretreatment selectively blocked cocaine-induced changes in extracellular GABA, but not in DA, in both naive rats and cocaine self-administration rats. These data suggest: (1) mGluR7 is critically involved in cocaine’s acute reinforcement; (2) GABA-, but not DA-, dependent mechanisms in the ventral striatopallidal pathway appear to underlie AMN082’s actions; and (3) AMN082 or other mGluR7-selective agonists may be useful in the treatment of cocaine addiction.
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影响因子：
7.6
作者：
Centonze, D;Picconi, B;Calabresi, P
通讯作者：
Calabresi, P
影响因子：
4.7
作者：
BOURDELAIS, AJ;KALIVAS, PW
通讯作者：
KALIVAS, PW
影响因子：
4.7
作者：
David, HN;Abraini, JH
通讯作者：
Abraini, JH
DOI：
10.1073/pnas.0508063102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Mitsukawa, K;Yamamoto, R;Flor, PJ
通讯作者：
Flor, PJ
影响因子：
56.9
作者：
KOOB, GF;BLOOM, FE
通讯作者：
BLOOM, FE