Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects.
Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects.
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DOI：
10.1523/jneurosci.1040-11.2011
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发表时间：
2011-08-03
期刊：
影响因子：
--
通讯作者：
Liu QS
中科院分区：
文献类型：
--
作者：
Pan B;Zhong P;Sun D;Liu QS
Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposure in vivo facilitates long-term potentiation in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid (eCB)-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for cocaine-induced reduction of GABAergic inhibition. The present study investigated the downstream signaling mechanisms and functional consequences of I-LTD in the VTA in the rat. Extracellular signal-regulated kinase (ERK) signaling has been implicated in long-term synaptic plasticity, associative learning and drug addiction. We tested the hypothesis that VTA ERK activity is required for I-LTD and cocaine-induced long-term synaptic plasticity and behavioral effects. We show that the activation of receptors required for I-LTD increased ERK1/2 phosphorylation and inhibitors of ERK activation blocked I-LTD. We further demonstrate that ERK mediates cocaine-induced reduction of GABAergic inhibition and facilitation of LTP induction. Finally, we show that cocaine conditioned place preference (CPP) training (15 mg/kg, 4 pairings) increased ERK1/2 phosphorylation in the VTA, while bilateral intra-VTA injections of a CB1 antagonist or an inhibitor of ERK activation attenuated ERK1/2 phosphorylation and the acquisition, but not the expression, of CPP to cocaine. Our study has identified the CB1 and ERK signaling cascade as a key mediator of several forms of cocaine-induced synaptic plasticity and provided evidence linking long-term synaptic plasticity in the VTA to rewarding effects of cocaine.
