STRESS AND ROLE OF PREFRONTAL CORTEX IN SENSITIZATION

前额皮质在敏化中的压力和作用

• 批准号: 2120681
• 负责人: Barbara A Sorg
• 金额: $ 8.32万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2120681
• 关键词: amphetamines; axon; behavioral habituation /sensitization; brain mapping; central nervous system stimulants; cocaine; dopamine; experimental brain lesion; extracellular; frontal lobe /cortex; laboratory rat; microdialysis; microinjections; neurochemistry; neurotransmitter metabolism; nucleus accumbens; stress; synaptosomes; tegmentum

Repeated exposure to psychostimulants, such as cocaine and amphetamine, produce an augmentation in the motor-stimulant response that increases with time, a phenomenon known as behavioral sensitization. Repeated exposure to stressful stimuli also produces an enhancement in the locomotor response to subsequent psychostimulants. the neurochemical changes underlying behavioral sensitization have focused on the mesocorticolimbic dopamine system, including the dopamine cell bodies in the ventral tegmental area (VTA) and projections to the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc). Recent cross-sensitization studies using in vivo microdialysis show that, in general, repeated stress or repeated cocaine augments the cocaine- or stress-induced increase in extracellular dopamine levels in the NAcc, while in the mPFC, an apparent tolerance to subsequent stimuli occurs. The augmentation in dopamine levels in the NAcc is known to be associated with behavioral sensitization but the inhibitory role of mPFC dopamine on locomotor activity has not been examined in the context of behavioral sensitization. The present studies propose to test the hypothesis that the apparent tolerance of mPFC neurons to subsequent stimuli contributes to the hyperlocomotion and associated increase in dopamine transmission in the NAcc in rats sensitized to repeated stress or cocaine. the first goal of this proposal is to characterize the changes that occur in extracellular dopamine levels in the mPFC following repeated footshock stress and repeated cocaine. In addition to measurement of basal dopamine levels in rats administered repeated stress and cocaine, in vivo dialysis measurements of mPFC extracellular dopamine levels will be performed following early, middle, and late withdrawal periods to determine if there are temporal changes in the tolerance effect. Secondly, mechanisms that may be mediating the tolerance effect in the mPFC will be examined in both the mPFC terminal field and in the dopamine cell body region in the VTA. The terminal field will be examined by local perfusion of K+, amphetamine, and cocaine through the dialysis probe. Additionally, dopamine reuptake will be tested in vitro in mPFC synaptosomes. Regulation by neurotransmitters in the VTA will be investigated by intra-VTA injection of NMDA, substance P and opioid agonists, and neurotensin, which modulate mPFC dopamine transmission. The final goal of this proposal is to determine the role of mPFC dopamine in the development and expression of behavioral and neurochemical sensitization. The first approach is to destroy mPFC dopamine terminals prior to repeated stress and cocaine treatment, and the second approach is to locally administer D1 and D2 receptor agonists into the mPFC just prior to a cocaine challenge to determine whether these treatments alter the levels of extracellular dopamine in the NAcc and associated increase in locomotor activity. Elucidation of the interactive role of mPFC dopamine in mediating sensitization to stress and cocaine has potential implications for understanding idiopathic as well as stress- and psychostimulant-precipitated psychoses, including paranoid schizophrenia, panic disorder, and posttraumatic stress disorder.

反复接触心理刺激剂，例如可卡因和苯丙胺， 在运动刺激反应中产生增强 随着时间的流逝，一种被称为行为敏化的现象。 重复 暴露于压力的刺激也会增加 运动对随后的心理刺激剂的反应。 神经化学 行为敏化的基本变化集中在 中皮质糖多巴胺系统，包括多巴胺细胞体 腹侧盖区域（VTA）和内侧前额叶的预测 皮质（MPFC）和伏隔核（NACC）。 最近的交叉敏化 使用体内微透析的研究表明，通常重复 压力或重复可卡因增加可卡因或应力诱导的 NACC中细胞外多巴胺水平的增加，而在MPFC中， 对随后的刺激有明显的耐受性。 增强 已知NACC中的多巴胺水平与行为有关 敏化但MPFC多巴胺在运动中的抑制作用 在行为方面尚未检查活动 致敏。 本研究建议检验以下假设 MPFC神经元对随后刺激的明显耐受性有助于 多巴胺传播的超局部和相关的增加 在NACC中，大鼠对重复应力或可卡因敏感。 第一个 该提议的目标是表征发生的变化 反复摇动后，MPFC中的细胞外多巴胺水平 压力和重复可卡因。 除了测量基础 大鼠的多巴胺水平施用重复应激和可卡因，体内 MPFC细胞外多巴胺水平的透析测量 在早期，中间和晚期撤回期之后进行 确定公差效果是否存在时间变化。 其次，可能正在介导耐受效应的机制 MPFC将在MPFC终端和多巴胺中进行检查 VTA中的细胞体区域。 终端字段将通过 通过透析的K+，苯丙胺和可卡因的局部灌注 探测。 此外，多巴胺再摄取将在MPFC中在体外测试 突触体。 VTA中神经递质的调节将是 通过注射NMDA，物质P和阿片类药物的VTA内注射。 激动剂和神经素，可调节MPFC多巴胺的传播。 该提案的最终目标是确定MPFC多巴胺的作用 在行为和神经化学的发展和表达中 致敏。 第一种方法是销毁MPFC多巴胺终端 在重复应力和可卡因治疗之前，第二种方法 是将D1和D2受体激动剂局部施加到MPFC中 在接受可卡因挑战之前，以确定这些治疗是否改变 NACC中细胞外多巴胺的水平以及相关的增加 在运动活动中。 阐明MPFC的互动作用 在介导对压力和可卡因的介导敏化中的多巴胺具有潜力 理解特发性以及压力和压力的影响 精神刺激性的精神病，包括偏执精神分裂症， 恐慌症和创伤后应激障碍。