Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism.
Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism.
复制标题
DOI：
10.1523/jneurosci.3625-11.2011
复制
发表时间：
2011-10-12
期刊：
影响因子：
--
通讯作者：
Tseng KY
中科院分区：
文献类型：
--
作者：
McCutcheon JE;Loweth JA;Ford KA;Marinelli M;Wolf ME;Tseng KY
在成年大鼠中，在延长的获取可卡因自我给药的长时间戒断后，高电导Ca 2+渗透性AMPA受体（CP-AMPAR）在延髓核（NAc）突触中积累并介导“孵育”线索诱导的可卡因渴求的表达。使用膜片钳记录从NAc切片制备后，延长访问可卡因自我管理和>45天的戒断，我们发现，第一组代谢型谷氨酸受体（mGluR）刺激使用3，5-二羟基苯甘氨酸（DHPG; 50μM）迅速消除突触后CP-AMPAR的NAc突触传递的贡献。这是伴随着Ca 2+不渗透的AMPAR（CI-AMPAR）介导的传输的促进，这表明DHPG可以促进CP-AMPAR和CI-AMPAR之间的交换。在生理盐水对照中，DHPG也减少兴奋性传递，但这是通过CB 1受体依赖性突触前机制发生的，而不是对突触后AMPAR的影响。阻断CB 1受体对可卡因组中DHPG产生的AMPAR传递的改变没有显著影响。有趣的是，可卡因组中DHPG的作用是由mGluR 1介导的，而其在盐水组中的作用是由mGluR 5介导的。这些结果表明，在NAc的突触传递的调节是深刻的改变后，延长访问可卡因自我管理和长期戒断。此外，他们认为mGluR 1的激活可能是减少戒断可卡因成瘾者对线索诱导的可卡因渴望的潜在策略。
Following prolonged withdrawal from extended access cocaine self-administration in adult rats, high conductance Ca2+-permeable AMPA receptors (CP-AMPARs) accumulate in nucleus accumbens (NAc) synapses and mediate the expression of “incubated” cue-induced cocaine craving. Using patch clamp recordings from NAc slices prepared after extended access cocaine self-administration and >45 days of withdrawal, we found that group I metabotropic glutamate receptor (mGluR) stimulation using 3,5-dihydroxyphenylglycine (DHPG; 50μM) rapidly eliminates the postsynaptic CP-AMPAR contribution to NAc synaptic transmission. This is accompanied by facilitation of Ca2+-impermeable AMPAR (CI-AMPAR)-mediated transmission, suggesting that DHPG may promote an exchange between CP-AMPARs and CI-AMPARs. In saline controls, DHPG also reduced excitatory transmission but this occurred through a CB1 receptor-dependent presynaptic mechanism rather than an effect on postsynaptic AMPARs. Blockade of CB1 receptors had no significant effect on the alterations in AMPAR transmission produced by DHPG in the cocaine group. Interestingly, the effect of DHPG in the cocaine group was mediated by mGluR1 whereas its effect in the saline group was mediated by mGluR5. These results indicate that regulation of synaptic transmission in the NAc is profoundly altered after extended access cocaine self-administration and prolonged withdrawal. Furthermore, they suggest that activation of mGluR1 may represent a potential strategy for reducing cue-induced cocaine craving in abstinent cocaine addicts.