Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior
Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior
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DOI：
10.1523/jneurosci.2828-16.2017
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发表时间：
2018-01-17
影响因子：
5.3
通讯作者：
Self, David W.
中科院分区：
文献类型：
--
作者：
Guzman, Daniel;Carreira, Maria B.;Self, David W.
可卡因自身给药增加腹侧被盖区（VTA）多巴胺神经元中GluA 1亚基的表达，这随后增强了可卡因的动机。GluA 1的这种增加可能依赖于伴随的NMDA受体（NMDAR）的激活，在自我管理，类似可卡因诱导的长时程增强的腹侧被盖区。在这项研究中，我们使用病毒介导的显性负性GluN 1亚基（HSV-dnGluN 1）在腹侧被盖区神经元的表达，研究短暂的NMDAR失活对慢性可卡因自我管理引起的GluA 1增加的影响。我们发现，dnGluN 1表达的VTA限制到3周的可卡因自我管理，防止随后增加组织GluA 1水平相比，对照组输注HSV-LacZ。令人惊讶的是，dnGluN 1表达导致自我施用可卡因的动机增强，如使用渐进比率强化时间表测量的，并且在延长的3周戒断期后的消退/恢复测试中测量的可卡因寻求增强。尽管阻断可卡因自我给药动物的组织GluA 1增加，但HSV-dnGluN 1治疗导致GluA 1和GluN 2B的膜水平增加，沿着对AMPA的VTA内输注的显著更高的运动反应，表明VTA AMPA受体反应性的矛盾增加。总之，这些数据表明，NMDAR介导可卡因诱导的VTA GluA 1表达的增加，但这种短暂的NMDAR失活也导致突触AMPA受体的补偿性缩放，增强可卡因的动机。
Cocaine self-administration increases expression of GluA1 subunits in ventral tegmental area (VTA) dopamine neurons, which subsequently enhance the motivation for cocaine. This increase in GluA1 may be dependent on concomitant NMDA receptor (NMDAR) activation during self-administration, similar to cocaine-induced long-term potentiation in the VTA. In this study, we used viral-mediated expression of a dominant-negative GluN1 subunit (HSV-dnGluN1) in VTA neurons to study the effect of transient NMDAR inactivation on the GluA1 increases induced by chronic cocaine self-administration in male rats. We found that dnGluN1 expression in the VTA limited to the 3 weeks of cocaine self-administration prevents the subsequent increase in tissue GluA1 levels when compared with control infusions of HSV-LacZ. Surprisingly, dnGluN1 expression led to an enhancement in the motivation to self-administer cocaine as measured using a progressive ratio reinforcement schedule and to enhanced cocaine seeking measured in extinction/reinstatement tests following an extended 3 week withdrawal period. Despite blocking tissue GluA1 increases in cocaine self-administering animals, the HSV-dnGluN1 treatment resulted in increased membrane levels of GluA1 and GluN2B, along with markedly higher locomotor responses to intra-VTA infusions of AMPA, suggesting a paradoxical increase in VTA AMPA receptor responsiveness. Together, these data suggest that NMDARs mediate cocaine-induced increases in VTA GluA1 expression, but such transient NMDAR inactivation also leads to compensatory scaling of synaptic AMPA receptors that enhance the motivational for cocaine.