Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons.
Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons.
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DOI：
10.1523/jneurosci.4773-08.2009
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发表时间：
2009-05-20
期刊：
影响因子：
--
通讯作者：
Bonci A
中科院分区：
文献类型：
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作者：
Hahn J;Hopf FW;Bonci A
目前的概念表明，应激诱导的神经调质释放，如促肾上腺皮质激素释放因子（CRF）可以驱动药物依赖性行为。虽然以前的药物暴露可以增强行为和神经化学反应的压力，目前还不清楚这种药物暴露如何改变CRF调制的兴奋性突触腹侧被盖区（VTA）多巴胺神经元，药物和压力诱导的神经适应的关键位点。在这里，我们证明，重复可卡因暴露后，CRF诱导的增强NMDA受体（NMDAR）介导的神经传递的幅度和持续时间显着增加相比，幼稚和盐水处理的小鼠。此外，CRF仅在暴露于可卡因的小鼠中增强AMPA受体（AMPAR）介导的传递。AMPAR介导的自发性微小EPSC的频率增加和CRF的细胞内阻断增强AMPAR介导的传递表明CRF的突触前和突触后作用。重要的是，药理学实验表明，CRF受体1和蛋白激酶A途径被重新招募后，重复可卡因的CRF诱导的NMDAR增强和AMPAR增强的外观。因此，增强CRF诱导的增强兴奋性突触传递到腹侧被盖区多巴胺神经元可卡因预暴露后，可能会产生异常增加多巴胺释放在应激事件，并可能增加激活成瘾行为的应激反应。
Current concepts suggest that stress-induced release of neuromodulators such as corticotropin-releasing factor (CRF) can drive drug-dependent behaviors. Although previous drug exposure can enhance behavioral and neurochemical responses to stress, it is unclear how such drug exposure alters the CRF modulation of excitatory synapses onto ventral tegmental area (VTA) dopamine neurons, a key locus of drug- and stress-induced neuroadaptation. Here, we demonstrate that, after repeated cocaine exposure, the magnitude and duration of the CRF-induced potentiation of NMDA receptor (NMDAR)-mediated neurotransmission was significantly increased compared with naive and saline-treated mice. Furthermore, CRF enhanced AMPA receptor (AMPAR)-mediated transmission only in mice that were exposed to cocaine. Increased frequency of AMPAR-mediated spontaneous miniature EPSCs and the intracellular blockade of CRF potentiation of AMPAR-mediated transmission suggest both presynaptic and postsynaptic effects of CRF. Importantly, pharmacological experiments revealed that CRF receptor 1 and protein kinase A pathways were newly recruited after repeated cocaine for the enhancement of CRF-induced NMDAR potentiation and the appearance of AMPAR potentiation. Thus, enhanced CRF-induced potentiation of excitatory synaptic transmission onto VTA dopamine neurons after cocaine preexposure is likely to produce an abnormal increase in dopamine release during stressful events and could augment activation of addictive behaviors in response to stress.