Heterogeneity of Ventral Tegmental Area Neurons and Opioid Reward

腹侧被盖区神经元的异质性和阿片类药物奖励

基本信息

批准号：
8582542
负责人：
Elyssa Margolis
金额：
$ 35.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8582542
关键词：
Accounting Agonist Alcohol consumption Alcoholism Anatomy Animals Attention deficit hyperactivity disorder Binge Eating Brain Data Disease Dopamine Electric Stimulation Elements Event Glutamates Goals Heterogeneity Hyperphagia Impulsivity In Situ Hybridization Label Lesion Measures Medial Mediating Microinjections Morphine National Institute of Drug Abuse Neurons Neurotransmitters Nucleus Accumbens Opiate Addiction Opiates Opioid Opioid Receptor Pathway interactions Physiological Population Prefrontal Cortex Property Receptor Activation Reporting Research Rewards Signal Transduction Slice Techniques Testing The Sun Ventral Striatum Ventral Tegmental Area Whole-Cell Recordings Work addiction alcohol reward brain pathway dopaminergic neuron endogenous opioids food consumption gamma-Aminobutyric Acid immunocytochemistry improved in vivo mu opioid receptors opioid abuse postsynaptic presynaptic public health relevance relating to nervous system research study response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Approximately 2 million people are dependent on or abuse opioids in the USA each year (www.dhhs.gov), and NIDA reports that illicit opiate use is on the rise. Accumulating evidence indicates that alcohol consumption and rewarding events cause the release of endogenous opioids in the brain, therefore utilizing the same mu opioid receptors (MORs) and brain circuits involved in opiate addiction. In spite of the magnitude of this problem, we only partially understand how MOR activation causes reward and leads to addiction. Therefore overall objective of this proposal is to investigate the circuits that contribute to opioid reward. MORs in the ventral tegmental area (VTA) are required for morphine reward (Olmstead and Franklin, 1997b; Zhang et al., 2009). VTA neurons release dopamine in the ventral striatum, and it is commonly thought that dopamine released in the ventral striatum causes opioid reward. Yet, lesions of the ventral striatum do not block morphine reward (Olmstead and Franklin, 1996, 1997a; White et al., 2005). Instead, lesions of the medial prefrontal cortex (mPFC) do block morphine reward (Tzschentke and Schmidt, 1999). Therefore the proposed experiments focus on MOR control of mPFC-projecting VTA neurons. Detailed anatomy of this projection will be studied, in particular to test whether the newly discovered VTA glutamate neurons project to the mPFC. Because morphine reward is dopamine-independent in opiate na¿ve animals (Bechara et al., 1992; Nader and van der Kooy, 1997), it is critical to determine the effects of MOR activation on both the non-dopamine and dopamine VTA neurons that project to the mPFC. Cortical-projecting neurons will be retrogradely labeled so that they can be identified during brain slice recordings, and pre- and postsynaptic MOR agonist effects will be measured electrophysiologically in these labeled neurons. Following recordings, the neurotransmitter content of the recorded neurons will be directly identified as dopamine, glutamate, or GABA using immunocytochemistry or in situ hybridization. Since electrical stimulation of the mPFC is rewarding (Corbett et al., 1982; Duvauchelle and Ettenberg, 1991), it is hypothesized that MOR activation will excite mPFC-projecting dopamine and glutamate neurons, and inhibit GABA neurons. By improving our understanding of the circuitry involved in opioid reward, this work will enable more effective therapeutic development for disorders that involve VTA and mPFC signaling, including addiction, alcoholism, impulsivity disorders and attention deficit hyperactivity disorder.

描述（由适用提供）：每年约有200万人依赖于美国的阿片类药物（www.dhhs.gov），而NIDA报告说，非法优化使用的使用正在上升。积累的证据表明，饮酒和奖励事件会导致大脑中内源性阿片类药物的释放，因此利用相同的MU阿片受体（MORS）和涉及优化成瘾的脑回路。尽管有这个问题的幅度，但我们只部分理解MOR激活如何引起奖励并导致成瘾。因此，该提案的总体目标是调查有助于阿片类药物奖励的电路。吗啡奖励需要腹侧对接区域（VTA）（VTA）（Olmstead和Franklin，1997b； Zhang等，2009）。 VTA神经元在腹侧纹状体中释放多巴胺，通常认为在腹侧纹状体中释放的多巴胺会导致OOid奖励。然而，腹纹状体的病变不会阻止吗啡奖励（Olmstead和Franklin，1996，1997a; White等，2005）。取而代之的是，中位前额叶皮层（MPFC）的病变会阻止吗啡奖励（Tzschentke and Schmidt，1999）。因此，提出的实验侧重于对MPFC投射VTA神经元的MOR控制。该投影的详细解剖结构将进行研究，特别是用于测试新发现的VTA谷氨酸神经元是否向MPFC进行。由于吗啡奖励是多巴胺在阿片类动物中与多巴胺无关的（Bechara等，1992; Nader and van der Kooy，1997），因此确定MOR激活对非多巴胺和多巴胺VTA神经元的影响至关重要。皮质预测的神经元将逆行标记，以便可以在脑切片记录中鉴定出它们，并且在这些标记的神经元中将通过电生理测量突触前和突触后的MONIST效应。以下记录，使用免疫细胞化学或原位杂交直接将记录神经元的神经递质含量直接鉴定为多巴胺，谷氨酸或GABA。由于MPFC的电刺激是奖励的（Corbett等，1982; Duvauchelle和Ettenberg，1991），因此假设MOR激活会激发MPFC-PROTORATION多巴胺和谷氨酸神经元，并抑制GABA神经元。通过提高我们对阿片类药物奖励所涉及的电路的理解，这项工作将使涉及VTA和MPFC信号传导的疾病的更有效的治疗性发育，包括加法，酒精中毒，冲动性疾病和注意力缺陷多功能障碍。