Nicotinic Modulation of the Mesoaccumbens DA System

Mesoaccembens DA 系统的烟碱调节

• 批准号: 6846558
• 负责人: Daniel S McGehee
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846558
• 关键词: acetylcholine; behavior test; dopamine; drug addiction; electrophysiology; gamma aminobutyrate; glucocorticoids; hormones; laboratory rat; neural transmission; neurons; nicotine; nicotinic receptors; nucleus accumbens; stress; synapses; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Nicotinic acetylcholine receptors (nAChRs) can modify synaptic transmission in many brain regions. Our recent studies show that nAChRs contribute to midbrain dopamine (DA) neuron excitability through modulation of both inhibitory GABAergic and excitatory glutamatergic inputs. The nAChR enhancement of glutamate inputs can contribute to LTP induction at this synapse. Interestingly, the nicotinic modulation of GABA transmission exhibits a transient enhancement, followed by a depression of activity. Apparently, desensitization of the nAChRs on GABA neurons inhibits endogenous cholinergic input to these cells, thus leading to a 'disinhibition' of the DA neurons. These studies were carried out in neonatal rats, primarily for technical reasons. Experiments in this proposal will extend these tests to tissue slices from adult rats that have undergone behavioral and pharmacological testing. The activity that an animal displays in a novel environment can predict nicotine self-administration in rats. The advantage of this screen is that animals predisposed to nicotine self-administration can be identified without nicotine exposure, which is known to alter sensitivity. Our preliminary results indicate differences in nAChR expression between high and low responders to novelty. We will extend these observations to test the differences in cellular and synaptic effects of nAChR activation associated with the predisposition to nicotine self-administration. The activity response to novelty has also been correlated with differences in stress hormone levels between individuals, leading to the suggestion that stress hormones contribute to the predisposition to drug-taking. Preliminary data indicate that stress hormones inhibit nAChRs through a direct interaction. We will test the hypothesis that this interaction upregulates the expression of nAChRs within the reward area, strengthens the cellular response to nicotine and thus, enhances the motivating effects of the drug. Nicotine exposure also enhances the acquisition of self-administration behavior, presumably through upregulation of nAChR expression. We will test nAChR effects on DA neuron excitability from animals that have been pre-exposed to nicotine by passive injection and self-administration testing. These studies of nAChR function within the brain reward center will provide important insights into the cellular basis of addiction.

描述（由申请人提供）：烟碱乙酰胆碱受体（nAChR）可以改变许多大脑区域的突触传递。我们最近的研究表明，nAChR 通过调节抑制性 GABA 能和兴奋性谷氨酸能输入来促进中脑多巴胺 (DA) 神经元的兴奋性。谷氨酸输入的 nAChR 增强有助于该突触处的 LTP 诱导。有趣的是，烟碱对 GABA 传输的调节表现出短暂的增强，随后活性降低。显然，GABA 神经元上的 nAChR 脱敏会抑制这些细胞的内源性胆碱能输入，从而导致 DA 神经元的“去抑制”。这些研究是在新生大鼠中进行的，主要是出于技术原因。该提案中的实验将把这些测试扩展到经过行为和药理学测试的成年大鼠的组织切片。动物在新环境中表现出的活动可以预测大鼠的尼古丁自我给药。这种筛查的优点是可以在不接触尼古丁的情况下识别出倾向于自我施用尼古丁的动物，众所周知，接触尼古丁会改变敏感性。我们的初步结果表明，对新鲜事物的高反应者和低反应者之间的 nAChR 表达存在差异。我们将扩展这些观察结果，以测试与尼古丁自我给药倾向相关的 nAChR 激活的细胞和突触效应的差异。对新奇事物的活动反应也与个体之间压力激素水平的差异相关，这表明压力激素会导致吸毒倾向。初步数据表明，应激激素通过直接相互作用抑制 nAChR。我们将测试这一假设，即这种相互作用上调奖励区域内 nAChR 的表达，增强细胞对尼古丁的反应，从而增强药物的激励作用。接触尼古丁还可能通过上调 nAChR 表达来增强自我给药行为的获得。我们将通过被动注射和自我给药测试来测试 nAChR 对预先暴露于尼古丁的动物的 DA 神经元兴奋性的影响。这些对大脑奖励中心内 nAChR 功能的研究将为成瘾的细胞基础提供重要的见解。