Dysregulation of Dopamine and Glutamate Release in the Prefrontal Cortex and Nucleus Accumbens Following Methamphetamine Self-Administration and During Reinstatement in Rats
Dysregulation of Dopamine and Glutamate Release in the Prefrontal Cortex and Nucleus Accumbens Following Methamphetamine Self-Administration and During Reinstatement in Rats
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DOI：
10.1038/npp.2013.231
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发表时间：
2014-03-01
影响因子：
7.6
通讯作者：
See, Ronald E.
中科院分区：
文献类型：
--
作者：
Parsegian, Aram;See, Ronald E.
甲基苯丙胺（冰毒）成瘾者往往表现出持久的认知和神经缺陷，这可能导致持续的药物寻求和高复吸率。这些缺陷可能与前额叶皮层（PFC）及其向丘脑核（NAc）的神经元投射的变化有关。在这里，我们在PFC和NAc在大鼠体内进行微透析后，无论是甲氨蝶呤自我管理或轭盐水控制的历史，以评估基线谷氨酸（GLU）水平，或恢复诱发的GLU和多巴胺（DA）流出在这两个地区同时在线索诱导，甲氨蝶呤引发，或结合线索甲氨蝶呤恢复条件。我们的研究结果表明，甲氨蝶呤自我给药（I）降低了基础GLU水平在两个dmPFC和NAc，（2）同时增加dmPFC和NAc GLU流出在恢复期间，（3）增加DA流出的dmPFC，但不是在NAc，在所有恢复条件下，与轭生理盐水对照。这些数据首次表明，精神兴奋剂自我管理的历史改变GLU稳态不仅在NAc，但也在dmPFC，其主要的GLU投影源。此外，组合的线索+甲基引发的恢复条件产生了mPFC和NAc细胞外GLU的最明显的增加，这表明线索和甲基引发条件在促进恢复中是加性的。最后，增加流出的DA在dmPFC，但不是在NAC，在整个恢复条件表明，DA释放在dmPFC可能是一个重要的介质的药物寻求发起的多重复发触发。
Methamphetamine (meth) addicts often exhibit enduring cognitive and neural deficits that likely contribute to persistent drug seeking and the high rates of relapse. These deficits may be related to changes in the prefrontal cortex (PFC) and its glutamatergic projections to the nucleus accumbens (NAc). Here, we performed in vivo microdialysis in the PFC and NAc in rats following either meth self-administration or yoked-saline control histories to assess baseline glutamate (GLU) levels, or reinstatement-evoked GLU and dopamine (DA) efflux in both regions simultaneously under cue-induced, meth-primed, or combined cues meth reinstatement conditions. Our results show that meth self-administration (I) reduced basal GLU levels in both the dmPFC and NAc, (2) concurrently increased dmPFC and NAc GLU efflux during reinstatement, and (3) increased DA efflux in the dmPFC, but not in the NAc, under all reinstatement conditions when compared with yoked-saline controls. These data demonstrate for the first time that a history of psychostimulant self-administration alters GLU homeostasis not only in the NAc, but also in the dmPFC, its primary GLU projection source. Furthermore, combined cues + meth-primed reinstatement conditions produced the most pronounced increases in mPFC and NAc extracellular GLU, suggesting that the cue and meth prime conditions are additive in promoting reinstatement. Finally, increased efflux of DA in the dmPFC, but not in the NAc, across reinstatement conditions suggests that DA release in the dmPFC may be an important mediator of drug seeking initiated by multiple relapse triggers.