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

描述（由申请人提供）：药物寻求行为成瘾模式的出现被认为是由大脑自然奖励和动机回路中的持续神经适应引起的，特别是复发期间的皮质类固醇和中皮质边缘回路。这一建议解决了甲基苯丙胺（甲基）滥用是否改变背内侧前额叶皮层（dmPFC）和神经核核心（NAc）细胞外谷氨酸和多巴胺的表达与可卡因和苯丙胺滥用在NAc中所见的一致的方式。此外，是否药物相关的线索，药物引发，或其组合诱导这些递质的表达的差异效应也将在体内微透析测量。我们假设甲安菲他明自我给药史会降低dmPFC和NAc中的基础谷氨酸和多巴胺水平（具体目标#1）。我们还预计这些变化将逆转（即，当给予大鼠甲基苯丙胺药物引发、呈现药物相关线索或两者结合时，与轭化盐水或盐水引发对照相比，NAc中的谷氨酸和DA两者都增加，而仅dmPFC中的多巴胺增加。确定甲基自我给药后dmPFC和NAc中谷氨酸的失调将解决甲基与可卡因以及谷氨酸和多巴胺的dmPFC和NAc表达是否存在差异。 公共卫生相关性：调查甲基苯丙胺滥用对背内侧前额叶皮层和背内侧前额叶核（与执行功能和成瘾有关的关键脑区）多巴胺和谷氨酸的神经化学平衡的影响，与公共卫生高度相关。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背后的神经化学变化，并将有助于确定广泛治疗人类成瘾者滥用，戒断和复发的新药物靶点。

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.