Opioid sensitive GABA outputs from the nucleus accumbens

伏隔核对阿片类药物敏感的 GABA 输出

• 批准号: 9060129
• 负责人: Brooks G Robinson
• 金额: $ 5.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060129
• 关键词: Acute; Adenosine; Agonist; Analgesics; Animals; Area; Asses; Back; Binding; Brain; Cells; Cholera Toxin; Chronic; Complex; Cues; Dependence; Development; Disinhibition; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug Tolerance; Equilibrium; Feedback; Future; Glean; Goals; Heterogeneity; Implant; Life; Mediating; Midbrain structure; Morphine; Morphine Dependence; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Receptor; Output; Pain; Pain management; Pharmaceutical Preparations; Phenotype; Property; Pump; Purinergic P1 Receptors; Rattus; Research; Rewards; Role; Signal Transduction; Slice; Synapses; System; Testing; Therapeutic Uses; Tracer; Ventral Tegmental Area; Withdrawal; addiction; cellular targeting; dopaminergic neuron; drug of abuse; endophenotype; gamma-Aminobutyric Acid; mu opioid receptors; neuromechanism; opioid use; postsynaptic; prescription opioid; public health relevance; receptor; relating to nervous system; response

 DESCRIPTION (provided by applicant): Morphine is the drug of choice when treating short-term moderate to severe pain. However, prolonged use often leads to the development of tolerance and eventually dependence. The neural mechanisms of these phenotypes are not fully understood. Acutely, morphine takes action on opioid receptors in the brain resulting in inhibition of the neurons containing the receptors. In the midbrain, agonist binding to opioid receptors on GABA neurons results in disinhibition of dopamine (DA) neurons. The resulting increase in DA release is thought to contribute to the rewarding and addicting aspects of opioids. Recent evidence indicates that there are several opioid-sensitive GABA inputs to midbrain DA neurons. One such GABAergic projection originates from medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and projects to the ventral tegmental area (VTA). Preliminary results indicate that both D1 and D2 DA receptor-expressing MSNs project to the VTA. These two sets of neurons express different opioid receptors (kappa and mu respectively) and synapse onto distinct target neurons. Additionally, the NAc projections target both DA and GABA neurons in the VTA. Previous research has shown that distinct opioid-sensitive inputs show different sensitivities to opioids as well as different levels of tolerance and withdrawal following chronic opioid exposure. The overall goal of this project is to characterize the two distinct NAc afferents to the VTA and discover how they change in response to acute and prolonged opioid exposure. The overall hypothesis is that the relative roles of the NAc afferent subsets will change following chronic morphine treatment. The specific aims of this proposal are as follows: (1) to identify the target neurons and target receptors in the VTA that receive input from each of the NAc projections, (2) to identify chronic morphine-induced adaptations in each of the NAc projections to the VTA, and (3) to determine the adaptations that occur in the GABAB-GIRK signaling complex in response to chronic morphine. Together, these aims will elucidate the role of the opioid-sensitive neural projection of GABAergic neurons in the NAc to the VTA in morphine dependence.

 描述（由申请人提供）：吗啡是治疗短期中度至重度疼痛的首选药物。然而，长期使用往往会导致耐受性的发展，并最终依赖。这些表型的神经机制尚未完全了解。吗啡对大脑中的阿片受体起作用，导致含有受体的神经元受到抑制。在中脑中，激动剂与GABA神经元上的阿片受体结合导致多巴胺（DA）神经元的去抑制。由此产生的DA释放的增加被认为有助于阿片类药物的奖励和成瘾方面。最近的证据表明，有几个阿片敏感的GABA输入中脑DA神经元。一种这样的GABA能投射起源于中脑背核（NAc）中的中型多刺神经元（MSN）并投射到腹侧被盖区（VTA）。初步结果表明，D1和D2 DA受体表达MSN项目的腹侧被盖区。这两组神经元表达不同的阿片受体（分别为kappa和mu），并与不同的靶神经元形成突触。此外，NAc投射靶向腹侧被盖区的DA和GABA神经元。先前的研究表明，不同的阿片类药物敏感性输入显示出对阿片类药物的不同敏感性，以及慢性阿片类药物暴露后不同水平的耐受性和戒断。该项目的总体目标是表征VTA的两种不同的NAc传入，并发现它们如何响应急性和长期阿片类药物暴露而变化。总的假设是，NAc传入亚群的相对作用将改变慢性吗啡治疗后。该提议的具体目标如下：（1）识别腹侧被盖区中接收来自每个NAc投射的输入的靶神经元和靶受体，（2）识别慢性吗啡诱导的腹侧被盖区的每个NAc投射的适应，以及（3）确定GABAB-GIRK信号复合体响应慢性吗啡而发生的适应。总之，这些目标将阐明阿片敏感的神经投射的GABA能神经元在NAc的VTA在吗啡依赖的作用。