CORTICAL REGULATION OF SENSITIZATION

描述：(改编自申请人的摘要) 反复暴露在精神刺激剂或压力下会产生进行性的 精神刺激剂诱导的运动活动持续增加 啮齿动物，一种称为行为敏感化的现象。 伏隔核细胞外多巴胺水平在 对应激或可卡因敏感的大鼠，而细胞外多巴胺 内侧前额叶皮质(MPFC)的水平降低。因此， MPFC中的多巴胺显示的是耐受性而不是敏感化 以应对随后的可卡因或压力挑战。由于多巴胺 在mPFC抑制mPFC兴奋性氨基酸(EAA)传出 皮质下部位并产生对刺激运动的抑制， 这个实验室最近的研究确定了对 MPFC多巴胺对可卡因或压力的反应可能有助于 运动活动的敏感化。MPFC的内部效应 微量注射D-苯丙胺对可卡因刺激的运动活动的影响 在对照组和可卡因致敏的大鼠身上进行了测量，结果 暗示着mPFC对表达 可卡因致敏。这些实验旨在测试 假设1)致敏鼠对mPFC多巴胺反应的耐受性 老鼠有助于行为敏感化的表达，而这 反应可能被mPFC中的谷氨酸重要地调制，和2) 反复应激和/或可卡因预处理会改变 将多巴胺激动剂注入mPFC以调节随后的 可卡因诱导的活动。拟议的工作将审查对 应激和可卡因诱导的行为敏感化的表达 由mPFC提出，重点是调节mPFC的多巴胺耐受和 它对行为产出的贡献。对于所有的研究，治疗 团体将幼稚、每日假电击、足部电击、生理盐水或可卡因。 第一个具体目标是调节压力--和可卡因-- 谷氨酸诱导mPFC对多巴胺的耐受。第二 特定的目标将检查局部致敏的调制 将多巴胺受体激动剂注入mPFC。第三 特定的目的将决定在哪条特定途径(S)中可能发生改变 应激和可卡因对行为敏感化的调节 关于从mPFC到伏核的EAA投射与。 从mPFC到腹侧被盖区(VTA)的传出。 将mPFC电路纳入敏化研究应 有助于加深对压力产生的机制的理解 使个人易于开始和恢复吸毒 行为和精神病患者。

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.