Impact of Meth Self-administration on GLU and DA in the Corticoaccumbens Pathway

描述(申请人提供)：吸毒成瘾行为模式的出现被认为是由于大脑自然奖赏和动机回路中持续的神经适应，特别是复发期间的皮质伏隔和中皮质边缘回路。该提案探讨了甲基苯丙胺(Meth)滥用是否会以一致的方式改变伏隔核背内侧前额叶皮质(DmPFC)和伏隔核核心(NAC)细胞外谷氨酸和多巴胺的表达，就像在NAC滥用可卡因和苯丙胺一样。此外，药物相关线索、药物原素或它们的组合是否会对这些递质的表达产生不同的影响，也将通过体内微透析来衡量。我们假设，冰毒自我给药史将降低dmPFC和NAC的基础谷氨酸和多巴胺水平(特定目标1)。我们还预计，这些变化将逆转(即，增加)NAC中的谷氨酸和多巴胺，而只有dmPFC中的多巴胺将增加，当给予大鼠冰毒，呈现与药物相关的线索，或与生理盐水或生理盐水启动的对照相比，药物相关提示或组合。确定冰毒自我给药后dmPFC和NAC中谷氨酸的异常调节将解决与可卡因以及dmPFC和NAC中谷氨酸和多巴胺的表达是否有差异的问题。 公共卫生相关性：调查滥用甲基苯丙胺对前额叶背侧皮质和伏隔核中多巴胺和谷氨酸的神经化学平衡的影响，这是涉及执行功能和成瘾的关键大脑区域，与公共健康高度相关。从这些研究中获得的新知识将有助于更好地了解甲基苯丙胺成瘾的神经化学变化，并将有助于确定新的药物治疗靶点，以广泛治疗人类成瘾者的滥用、戒断和复发。

DESCRIPTION (provided by applicant): The emergence of addictive patterns of drug-seeking behavior is thought to arise from persistent neuroadaptations in the natural reward and motivation circuits of the brain, particularly the corticoaccumbens and mesocorticolimbic circuitry during relapse. This proposal addresses whether methamphetamine (meth) abuse alters dorsal medial prefrontal cortex (dmPFC) and nucleus accumbens core (NAc) extracellular glutamate and dopamine expression in a consistent manner as seen with cocaine and amphetamine abuse in the NAc. In addition, whether drug associated cues, drug prime, or their combination induce differential effects on expression of these transmitters will also be measured with in vivo microdialysis. We hypothesize that a history of meth self-administration will decrease both basal glutamate and dopamine levels in the dmPFC and NAc (Specific Aim #1). We also expect that these changes will reverse (i.e., increase) both glutamate and DA in the NAc, while dopamine will increase in the dmPFC only, when rats are given a meth drug-prime, presented with drug-associated cues, or the combination, as compared to yoked-saline or saline primed controls. Identifying the dysregulation of glutamate in both the dmPFC and NAc after meth self-administration would address whether there are differences with meth than cocaine and the dmPFC and NAc expression of glutamate and dopamine. PUBLIC HEALTH RELEVANCE: The investigation of the impact of methamphetamine abuse on the neurochemical balance of dopamine and glutamate in the dorsal medial prefrontal cortex and nucleus accumbens, critical brain areas involved in executive function and addiction, is highly relevant to public health. New knowledge gained from these studies will contribute to a better understanding of the neurochemical changes that underlie methamphetamine addiction and will help identify novel pharmacotherapeutic targets for broadly treating abuse, withdrawal, and relapse in human addicts.