Acute cocaine exposure weakens GABA(B) receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area.
Acute cocaine exposure weakens GABA(B) receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area.
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DOI：
10.1523/jneurosci.0494-11.2011
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发表时间：
2011-08-24
期刊：
影响因子：
--
通讯作者：
Wickman K
中科院分区：
文献类型：
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作者：
Arora D;Hearing M;Haluk DM;Mirkovic K;Fajardo-Serrano A;Wessendorf MW;Watanabe M;Luján R;Wickman K
由单次可卡因注射触发的腹侧被盖区（VTA）多巴胺（DA）神经元中的增强的多巴胺能神经传递代表了与成瘾特征的滥用药物的更持久影响相关的早期适应。在这里，我们研究了体内可卡因暴露对涉及腹侧被盖区DA神经元G蛋白门控内向整流K+（Girk）通道的促代谢抑制信号的影响。GABAB受体（GABABR）激动剂巴氯芬诱发的体树突Girk电流在给予单次可卡因注射的小鼠中以剂量依赖性方式减少。这种适应持续3-4天，是特定的腹侧被盖区的DA神经元，并发生在平行的自发性多巴胺能神经传递的增加。重复可卡因给药后，未观察到GABABR-Girk信号传导的额外抑制。虽然总Girk 2和GABABR 1的mRNA和蛋白水平没有改变可卡因暴露在腹侧被盖区DA神经元，可卡因诱导的GABABR-Girk信号的减少与减少在腹侧被盖区DA神经元的质膜上的Girk 2通道。舒必利全身性预处理，但不是SCH 23390，防止可卡因诱导的抑制GABABR-Girk信号，牵连D2/3 DA受体激活在这种适应。急性可卡因诱导的体树突Girk信号的减弱补充了先前证明的可卡因诱导的多巴胺能神经传递的加强，可能有助于在成瘾的早期阶段增强腹侧被盖区DA神经元的输出。
Enhanced glutamatergic neurotransmission in dopamine (DA) neurons of the ventral tegmental area (VTA), triggered by a single cocaine injection, represents an early adaptation linked to the more enduring effects of abused drugs that characterize addiction. Here, we examined the impact of in vivo cocaine exposure on metabotropic inhibitory signaling involving G protein-gated inwardly-rectifying K+ (Girk) channels in VTA DA neurons. Somatodendritic Girk currents evoked by the GABAB receptor (GABABR) agonist baclofen were diminished in a dose-dependent manner in mice given a single cocaine injection. This adaptation persisted for 3-4 days, was specific for DA neurons of the VTA, and occurred in parallel with an increase in spontaneous glutamatergic neurotransmission. No additional suppression of GABABR-Girk signaling was observed following repeated cocaine administration. While total Girk2 and GABABR1 mRNA and protein levels were unaltered by cocaine exposure in VTA DA neurons, the cocaine-induced decrease in GABABR-Girk signaling correlated with a reduction in Girk2-containing channels at the plasma membrane in VTA DA neurons. Systemic pre-treatment with sulpiride, but not SCH23390, prevented the cocaine-induced suppression of GABABR-Girk signaling, implicating D2/3 DA receptor activation in this adaptation. The acute cocaine-induced weakening of somatodendritic Girk signaling complements the previously-demonstrated cocaine-induced strengthening of glutamatergic neurotransmission, likely contributing to enhanced output of VTA DA neurons during the early stages of addiction.