CORTICAL REGULATION OF SENSITIZATION

描述：（改编自申请人摘要） 反复暴露于精神兴奋剂或压力会产生渐进性 并持续增加精神兴奋剂诱导的运动活动， 啮齿动物，一种被称为行为敏化的现象。 中脑腹外侧核的细胞外多巴胺水平增强， 对应激或可卡因敏感的大鼠，而细胞外多巴胺 内侧前额叶皮层（mPFC）的水平降低。因此，在本发明中， mPFC中的多巴胺表现出耐受性而非致敏性 对随后的可卡因或压力挑战的反应。自从多巴胺 抑制mPFC兴奋性氨基酸（EAA）的传出， 皮质下部位并产生对受刺激运动的抑制， 该实验室最近的研究确定了 mPFC多巴胺对可卡因或压力的反应性可能有助于 自发活动的敏感化。内mPFC的影响 微量注射d-苯丙胺对可卡因刺激的自发活动的影响 在对照组和可卡因致敏大鼠中测量，结果 建议mPFC为表达以下内容做出重要贡献： 可卡因致敏这些实验旨在测试 假设：1）致敏的mPFC多巴胺反应的耐受性 大鼠有助于行为敏感化的表达， mPFC中的谷氨酸可能对反应有重要的调节作用，以及2） 反复的压力和/或可卡因预处理改变了 多巴胺激动剂注入mPFC，调节随后的 可卡因引起的活动拟议的工作将审查监管， 应激和可卡因诱导的行为敏感化的表达 通过mPFC，重点是调节mPFC多巴胺耐受性， 它对行为输出的贡献。对于所有研究，治疗 组将是未处理的、每日假休克、足休克、盐水或可卡因。 第一个具体目标集中在调节压力和可卡因- 谷氨酸诱导mPFC中多巴胺耐受。第二 具体目标将审查地方政府对敏感性调节 向mPFC中施用多巴胺受体激动剂。第三 具体目标将决定在细胞中可以改变哪些具体途径， 调节对压力和可卡因的行为敏感性， 关于从mPFC到延髓核的EAA投射， 这些传出从mPFC到腹侧被盖区（VTA）。 将mPFC电路纳入致敏研究应 从而加深对压力机制的理解， 使个人倾向于开始和恢复吸毒 行为和精神病。

DESCRIPTION: (Adapted From The Applicant's Abstract) Repeated exposure to psychostimulants or stress produces a progressive and enduring increase in psychostimulant-induced locomotor activity in rodents, a phenomenon referred to as behavioral sensitization. Extracellular dopamine levels in the nucleus accumbens are enhanced in rats sensitized to stress or cocaine, while extracellular dopamine levels in the medial prefrontal cortex (mPFC) are diminished. Thus, dopamine in the mPFC demonstrates tolerance rather than sensitization in response to a subsequent cocaine or stress challenge. Since dopamine in the mPFC inhibits mPFC excitatory amino acid (EAA) efferents to subcortical sites and produces inhibition of stimulated locomotion, recent studies in this laboratory determined whether the tolerance of mPFC dopamine responsiveness to cocaine or stress may contribute to sensitization of locomotor activity. The effects of intra-mPFC microinjection of d-amphetamine on cocaine-stimulated locomotor activity was measured in control and cocaine sensitized rats, and the results suggest an important contribution by the mPFC for the expression of cocaine sensitization. The experiments are designed to test the hypotheses that 1) tolerance of the mPFC dopamine response in sensitized rats contributes to the expression of behavioral sensitization, and this response may be importantly modulated by glutamate in the mPFC, and 2) repeated stress and/or cocaine pretreatment alter the ability of dopamine agonists administered into the mPFC to regulate subsequent cocaine-induced activity. The proposed work will examine regulation of the expression of stress- and cocaine-induced behavioral sensitization by the mPFC with emphasis on regulation of mPFC dopamine tolerance and its contribution to behavioral output. For all studies, the treatment groups will be naive, daily sham shock, foot shock, saline or cocaine. The first specific aim focuses on the modulation of stress- and cocaine- induced tolerance of dopamine in the mPFC by glutamate. The second specific aim will examine modulation of sensitization by local administration of dopamine receptor agonists into the mPFC. The third specific aim will determine which specific pathway(s) may be altered in the regulation of behavioral sensitization to stress and cocaine with regard to EAA projections from the mPFC to the nucleus accumbens vs. those efferents from the mPFC to the ventral tegmental area (VTA). Incorporation of the mPFC circuitry into sensitization studies should lead to an increased understanding of the mechanisms by which stress predisposes individuals to initiation and reinstatement of drug taking behavior and psychoses.