NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization
NMDA Receptors on Non-Dopaminergic Neurons in the VTA Support Cocaine Sensitization
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DOI：
10.1371/journal.pone.0012141
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发表时间：
2010-08-16
期刊：
影响因子：
3.7
通讯作者：
Backman, Cristina M.
中科院分区：
文献类型：
--
作者：
Luo, Yu;Good, Cameron H.;Backman, Cristina M.
背景资料：可卡因和其他精神兴奋剂的行为敏化的启动被认为反映了中脑边缘多巴胺（DA）回路中N-甲基-D-天冬氨酸受体（NMDAR）介导的突触可塑性。最近，在表达Cre重组酶的DA神经元中缺乏功能性NMDAR的Cre-loxp小鼠中，评价了药物诱导的NMDAR介导的腹侧被盖区（VTA）DA神经元适应的重要性及其与药物寻求行为的关联，所述重组酶受内源性多巴胺转运蛋白基因的控制方法和主要发现：使用另外的NR 1（DATCre）小鼠转基因模型，我们证明了虽然DA神经元中NMDAR的选择性失活消除了导致突触强化的分子变化的诱导，在NR 1（DATCre）小鼠中，诸如可卡因诱导的运动敏感和条件性位置偏爱的行为测量保持完整。由于投射到前额皮质和杏仁核的腹侧被盖区DA神经元表达很少或没有可检测水平的多巴胺转运蛋白，因此推测投射到这些脑区的DA神经元中的NMDA受体可能在NR 1（DATCre）小鼠中幸免。在这里，我们证明了NMDA受体基因在大多数腹侧被盖区DA神经元中被消融，包括那些在我们的NR 1（DATCre）转基因模型中表现出不可检测的DAT表达水平的神经元，并且在NR 1（DATCre）动物的腹侧被盖区内应用NMDAR拮抗剂仍然阻断对可卡因的致敏。这些结果排除了NR 1（DATCre）小鼠模型中不同DA神经元亚群中NMDAR介导的神经可塑性的可能性，因此表明非DA神经元上的NMDAR介导的神经可塑性可能是神经可塑性的一部分。腹侧被盖区的多巴胺能神经元在可卡因成瘾行为中起着重要作用。
Background: The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA) DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre) mice).Methodology and Principal Findings: Using an additional NR1(DATCre) mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre) mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre) mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine.Conclusions/Significance: These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre) mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.