Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Department of Pharmacological Sciences, Institute for Systems Biomedicine, and.
J Neurosci. 2018 Jan 17;38(3):575-585. doi: 10.1523/JNEUROSCI.2828-16.2017. Epub 2017 Dec 1.
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. Dopamine neurons in the ventral tegmental area (VTA) are critical substrates of drug rewards. Animal models indicate that chronic cocaine use enhances excitatory glutamatergic input to these neurons, making them more susceptible to environmental stimuli that trigger drug craving and relapse. We previously found that self-administration of cocaine increases AMPA glutamate receptors in the VTA, and this effect enhances motivation for cocaine. Here we report that the mechanism for this upregulation involves NMDA receptor activity during cocaine use. While interference with NMDA receptor function blocks AMPA receptor upregulation, it also produces a paradoxical enhancement in membrane AMPA receptor subunits, AMPA responsiveness, and the motivation for cocaine. Thus, pharmacotherapy targeting NMDA receptors may inadvertently produce substantial adverse consequences for cocaine addiction.
可卡因自我给药会增加腹侧被盖区（VTA）多巴胺神经元中 GluA1 亚基的表达，进而增强对可卡因的动机。这种 GluA1 的增加可能依赖于自我给药过程中伴随的 NMDA 受体（NMDAR）激活，类似于 VTA 中可卡因诱导的长期增强。在这项研究中，我们使用病毒介导的 VTA 神经元中显性负性 GluN1 亚基（HSV-dnGluN1）的表达来研究短暂性 NMDAR 失活对慢性可卡因自我给药诱导的雄性大鼠 GluA1 增加的影响。我们发现，与 HSV-LacZ 的对照输注相比，仅在可卡因自我给药的 3 周内表达 VTA 中的 dnGluN1 可防止随后组织 GluA1 水平的增加。令人惊讶的是，dnGluN1 表达导致使用递增比率强化方案测量的可卡因自我给药动机增强，并且在延长的 3 周戒断期后，在消退/重新激发测试中增强可卡因寻求。尽管阻断可卡因自我给药动物的组织 GluA1 增加，但 HSV-dnGluN1 处理导致 VTA 内 AMPA 输注时 GluA1 和 GluN2B 的膜水平升高，以及明显更高的运动反应，表明 VTA AMPA 受体反应性出现悖论性增加。总之，这些数据表明 NMDAR 介导可卡因诱导的 VTA GluA1 表达增加，但这种短暂性 NMDAR 失活也会导致突触 AMPA 受体的代偿性缩放，从而增强对可卡因的动机。腹侧被盖区（VTA）中的多巴胺神经元是药物奖励的关键底物。动物模型表明，慢性可卡因使用会增强这些神经元的兴奋性谷氨酸能输入，使它们更容易受到引发药物渴望和复发的环境刺激的影响。我们之前发现，可卡因的自我给药会增加 VTA 中的 AMPA 谷氨酸受体，并且这种作用会增强对可卡因的动机。在这里，我们报告说，这种上调的机制涉及可卡因使用期间 NMDA 受体活性。虽然干扰 NMDA 受体功能会阻止 AMPA 受体上调，但它也会产生膜 AMPA 受体亚基、AMPA 反应性和可卡因动机的悖论性增强。因此，针对 NMDA 受体的药物治疗可能会无意中给可卡因成瘾带来重大不利后果。
