Nicotinic Modulation of the Mesoaccumbens DA System

描述(申请人提供)：烟碱型乙酰胆碱受体(NAChRs)可以改变许多大脑区域的突触传递。我们最近的研究表明，nAChRs通过调节抑制性GABA能和兴奋性谷氨酸能输入，促进中脑多巴胺(DA)神经元的兴奋性。谷氨酸输入的nAChR增强可能有助于在该突触诱导LTP。有趣的是，烟碱对GABA传递的调节表现出短暂的增强，然后是活性的抑制。显然，GABA神经元上nAChRs的脱敏抑制了内源性胆碱能对这些细胞的输入，从而导致DA神经元的“去抑制”。这些研究是在新生大鼠身上进行的，主要是出于技术原因。这项提议中的实验将把这些测试扩展到成年大鼠的组织切片，这些组织切片已经接受了行为和药理学测试。动物在新环境中表现出的活动可以预测大鼠体内尼古丁的自我给药。这种筛查的优点是，易于尼古丁自我给药的动物可以在没有尼古丁暴露的情况下被识别出来，众所周知，尼古丁暴露会改变敏感性。我们的初步结果表明，nAChR的表达在对新奇事物的高反应者和低反应者之间存在差异。我们将扩展这些观察，以测试nAChR激活与尼古丁自我给药易感性相关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荷尔蒙水平的差异有关，这导致了压力荷尔蒙对吸毒易感性的影响。初步数据表明，应激激素通过直接相互作用抑制nAChRs。我们将检验这一假设，即这种相互作用上调了奖赏区域内nAChRs的表达，增强了细胞对尼古丁的反应，从而增强了药物的激励作用。尼古丁暴露也增强自我给药行为的获得，可能是通过上调nAChR的表达。我们将通过被动注射和自我给药测试，测试nAChR对预先暴露于尼古丁的动物DA神经元兴奋性的影响。这些对大脑奖赏中心内nAChR功能的研究将为成瘾的细胞基础提供重要的见解。

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.