A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens
A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens
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DOI：
10.1523/jneurosci.0671-04.2004
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发表时间：
2004-08-04
影响因子：
5.3
通讯作者：
Manzoni, OJ
中科院分区：
文献类型：
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作者：
Fourgeaud, L;Mato, S;Manzoni, OJ
在伏隔核(NAC)中，突触前大麻素CB1受体(CB1Rs)和突触后代谢型谷氨酸5受体(MGluR5s)是内源性大麻素(ECB)介导的逆行性长期抑郁(LTD)(ECB-LTD)在前额叶皮质-NAC突触的主要效应者。CB1R和mGluR5都参与了可卡因相关的行为；然而，体内可卡因暴露对ECB介导的突触逆行可塑性的影响仍不清楚。使用了电生理和生化方法，我们报告了一次体内可卡因注射废除了ECB-LTD。可卡因的这种作用在D(1)多巴胺受体(D1R)-/-小鼠中不存在，当可卡因与选择性D1R拮抗剂8-chloro-2，3，4，5-tetrahydro-3-5-1h-3-benzazepin-7-ol(0.50 mg/kg)或NMDAR阻断剂(+)-5-甲基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺马来酸(1 mg/kg)联合使用时，可卡因的这种作用被阻止，这表明D1R和NMDAR参与了可卡因的作用。我们发现，可卡因诱导的逆行信号阻断与含有卷曲卷曲结构域的Hmer支架蛋白表达水平的增强相关，并伴随着mGluR5表面表达的强烈降低。这些结果表明，可卡因诱导的ECB逆行信号的丧失是由于mGluR5将顺行谷氨酸传递转化为ECB逆行信号的能力降低所致。
In the nucleus accumbens (NAc), a key structure to the effects of all addictive drugs, presynaptic cannabinoid CB1 receptors (CB1Rs) and postsynaptic metabotropic glutamate 5 receptors (mGluR5s) are the principal effectors of endocannabinoid (eCB)-mediated retrograde long-term depression (LTD) (eCB-LTD) at the prefrontal cortex-NAc synapses. Both CB1R and mGluR5 are involved in cocaine-related behaviors; however, the impact of in vivo cocaine exposure on eCB-mediated retrograde synaptic plasticity remains unknown. Electrophysiological and biochemical approaches were used, and we report that a single in vivo cocaine administration abolishes eCB-LTD. This effect of cocaine was not present inD(1) dopamine receptor (D1R)-/- mice and was prevented when cocaine was coadministered with the selective D1R antagonist 8-chloro-2,3,4,5-tetrahydro-3-5-1h-3-benzazepin-7-ol (0.5 mg/kg) or with the NMDA receptor (NMDAR) blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine maleate (1 mg/kg), suggesting the involvement of D1R and NMDAR. We found that the cocaine-induced blockade of retrograde signaling was correlated with enhanced expression levels of Homer scaffolding proteins containing the coiled-coil domain and accompanied by a strong reduction of mGluR5 surface expression. The results suggest that cocaine-induced loss of eCB retrograde signaling is caused by a reduction in the ability of mGluR5 to translate anterograde glutamate transmission into retrograde eCB signaling.