STRUCTURAL SITES FOR OPIATE MODULATION OF FRONTAL CORTEX

额叶皮层阿片调节的结构位点

• 批准号: 2821807
• 负责人: ADENA L SVINGOS
• 金额: $ 23.47万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2821807
• 关键词: acetylcholine; dopamine; frontal lobe /cortex; gamma aminobutyrate; immunoelectron microscopy; innervation; laboratory rat; nerve endings; neuroanatomy; neurochemistry; neuropharmacology; opiate alkaloid; opioid receptor; protein localization; substance abuse related behavior

DESCRIPTION: (Adapted From The Applicant's Abstract) Activation of mu (MOR) and delta opioid receptors (DOR) produces the motivational behaviors that are concomitant with opiate addiction. The complex neuronal adaptations associated with these behaviors are thought to be mediated through opiate targeting of GABAergic and cholinergic neurons that are either located within the medial prefrontal cortex (mPFC), or in other brain regions that provide major cortical innervation. To determine the cellular sites for opiate modulation of mPFC transmission through activation of MOR and DOR, we will combine dual-labeling electron microscopic immunocytochemistry, retrograde tract-tracing and in vivo intracellular and extracellular single-unit recording in rat brain. Study 1 will test whether MOR and DOR are localized to 1) specific neuronal compartments within GABAergic cells of the mPFC, 2) cell bodies that project directly from the VTA to the mPFC that are known to contain dopamine and possibly GABA, and 3) axon terminals in the VTA that innervate projection neurons to the mPFC. Results from this study will establish potential functional sites for opiate modulation of MPFC transmission through activation of MOR and DOR located on selective sites of local GABAergic neurons or projection cells from the VTA. Study 2 will test the hypotheses that MOR and DOR are located on either 1) cholinergic terminals or their targets within MPFC, or 2) basal forebrain cell bodies that are known to contain acetylcholine, and also project to the MPFC. Results from this study will establish whether opiate modulation of cortical cholinergic transmission is likely to occur through changes in local presynaptic release of acetylcholine, the receptivity of cholinergic targets, or activation of extrinsic projection neurons. Study 3 will test the hypothesis that neurons in the VTA that are physiologically characterized as non-dopaminergic, contain GABA, MOR and/or DOR. This study will establish the neurotransmitter in physiologically identified VTA neurons, and also will determine the functional sites for opiates within putative GABAergic neurons in the VTA. These integrative studies will determine the cellular sites for opiate targeting of MOR and DOR within anatomically and physiologically identified neurons involved in modulation of the MPFC. Results from these studies are important for establishing the disinhibitory circuits involved in the motivational aspects of opiate use. Elucidating the chemical identity of cortical and midbrain targets of opiates that are active at MOR and DOR are crucial for clinical intervention during opiate craving and withdrawal.

描述：（根据申请人的摘要改编） Mu（MOR）和三角洲阿片受体（DOR）的激活产生 与鸦片成瘾伴随的动机行为。这 认为与这些行为相关的复杂神经元适应 通过鸦片靶向GABA能和胆碱能的靶向介导 位于内侧前额叶皮层内的神经元 （MPFC），或在提供主要皮质的其他大脑区域 神经。确定用于阿片类鸦片调制的细胞位点 MPFC通过激活MOR和DOR传输，我们将结合 双标签电子显微镜免疫细胞化学，逆行 道追踪和体内细胞内和细胞外单单元 记录大鼠大脑。研究1将测试MOR和DOR是否 位于1）GABA能细胞中的特定神经元室 MPFC的2）直接从VTA发射到的细胞体 已知包含多巴胺和可能的GABA的MPFC，以及3）轴突 VTA中的末端将投影神经元支配到MPFC。 这项研究的结果将建立潜在的功能部位 通过激活MOR和DOR的激活MPFC传输的鸦片调制 位于局部GABA能神经元的选择性部位或投影 来自VTA的细胞。研究2将检验MOR和DOR的假设 位于1）胆碱能终端或其目标 MPFC，或2）已知包含的基础前脑细胞体 乙酰胆碱，还投射到MPFC。这项研究的结果 将确定鸦片是否可以调节皮质胆碱能的调节 传播可能通过局部突触的变化发生 乙酰胆碱的释放，胆碱能靶标的接受度或 外部投影神经元的激活。研究3将测试 VTA中的神经元在生理上是假设 被特征为非羟胺能，包含GABA，MOR和/或DOR。这 研究将在生理上鉴定的神经递质建立神经递质 VTA神经元，还将确定阿片类药物的功能部位 在VTA中的假定GABA能神经元中。这些综合研究 将确定用于鸦片靶向MOR和DOR的细胞位点 在解剖学和生理上鉴定的神经元中 MPFC的调制。这些研究的结果对于 建立激励性涉及的抑制回路 鸦片使用的各个方面。阐明皮质和 在MOR和DOR中活跃的阿片类药物的中脑目标至关重要 在鸦片渴望和戒断期间进行临床干预。