Role of mesopontine cholinergic afferents in methamphetamine reward

描述(申请人提供)：药物寻找和奖励的特征可以是腹侧被盖区(VTA)中多巴胺(DA)神经元的突然放电和中皮质边缘通路中DA释放的增加。其他神经递质，如乙酰胆碱(ACh)，作用于VTA，增加伏隔核(NAC)区域的DA释放。ACh还调节滥用药物的行为强化特征。我们的实验室最近发现，甲基苯丙胺(MA)增加了VTA中的ACh和DA。VTA主要接受来自桥中脑区的ACh连接，该区域被称为外侧背被盖(LDT)，当激活时，可以增加DA的活性，并在通路的其他区域诱导释放。因此，LDT胆碱能神经元可能参与了MA引起的DA和ACh的升高。此外，VTA内ACh音调可能调节MA寻求行为。本研究的目的是从LDT分离ACh投射到VTA，以确定其在MA对小鼠的神经化学效应(特异性目标1)和行为效应(特异性目标2)中的重要性。第一个目的将确定LDT ACh连接在MA诱导的ACh和DA增加中的作用。在这项实验中，我将可逆地失活LDT与VTA的ACh连接，并使用微透析来测量小鼠VTA中的DA和ACh。我预计LDT ACh的失活将阻断MA诱导的VTA中ACh和DA的增加。第二个目标将确定LDT ACH在恢复到MA-SEQUEING时向VTA提供的投入。在这个实验中，我将训练小鼠自我给药MA，然后消除这种行为。通常，在物种灭绝后，小剂量的MA将恢复寻找MA的行为。在给药之前，我将可逆地使LDT ACh连接失活。我预计这种对ACh的抑制将阻止MA诱导的药物寻找的恢复。MA成瘾的持续药物寻找特征是由中皮质边缘通路中广泛的神经化学环境的相互作用所维持的。尽管ACh被发现与奖赏和MA相关行为密切相关，但LDT ACh投射到VTA在MA寻求行为中的作用尚不清楚。这项建议结合神经化学和行为方法来定义这种胆碱能投射如何影响VTA内的神经化学环境，并最终影响MA的寻求。 与公共卫生相关：甲基苯丙胺成瘾的一个特别脆弱的阶段是在一段戒断期之后，此时启动剂量的药物或暴露于以前与药物配对的刺激(提示)可导致复发。为了开发更有效的治疗策略，了解恢复甲基苯丙胺寻找行为的神经化学基础是重要的。这项提议将使用行为和神经化学技术的组合来确定驱动甲基苯丙胺寻求的神经化学底物。

DESCRIPTION (provided by applicant): Drug seeking and reward can be characterized by the burst firing of dopamine (DA) neurons in the ventral tegmental area (VTA) and increased DA release within the mesocorticolimbic pathway. Other neurotransmitters, such as acetylcholine (ACh), act in the VTA to increase DA release in an area of the pathway called the nucleus accumbens (NAc). ACh also mediates the behaviorally reinforcing characteristics of drugs of abuse. Our lab recently found that methamphetamine (MA) increases ACh and DA in VTA. The VTA primarily receives ACh connections from a mesopontine region known as the laterodorsal tegmentum (LDT) that when active can increase DA activity and induce release in other regions of the pathway. Thus, LDT cholinergic neurons may be involved in MA-induced increases in DA and ACh. Further, the intra-VTA ACh tone may mediate MA-seeking behaviors. The goals of this research involve isolating the ACh projection from the LDT to the VTA in order to determine its importance in the neurochemical (Specific Aim 1) and behavioral (Specific Aim 2) effects of MA in mice. The first aim will determine the involvement of the LDT ACh connection on MA-induced increases in ACh and DA. In this experiment I will reversibly inactivate the LDT ACh connection to the VTA and use microdialysis to measure DA and ACh in the VTA of mice. I anticipate that the inactivation of the LDT ACh will block MA-induced increases in ACh and DA in the VTA. The second aim will determine the involvement of the LDT ACh input to the VTA on reinstatement to MA-seeking. In this experiment I will train mice to self-administer MA and then extinguish this behavior. Typically after extinction a small priming dose of MA will reinstate MA- seeking behavior. Before this MA priming dose is administered I will reversibly inactivate the LDT ACh connection. I anticipate this inhibition of ACh will block MA-primed reinstatement to drug seeking. Persistent drug-seeking characteristic of MA addiction is maintained by the interactions of a wide neurochemical milieu within the mesocorticolimbic pathway. Although ACh has been found to be critically involved in reward and MA-related behaviors, the role of the LDT ACh projections to the VTA in MA-seeking behavior has yet to be characterized. This proposal combines neurochemical and behavioral approaches to define how this cholinergic projection affects the neurochemical environment within the VTA and ultimately affect MA-seeking. PUBLIC HEALTH RELEVANCE: A particularly vulnerable phase of methamphetamine addiction is following a period of abstinence when a priming dose of the drug or exposure to previously drug-paired stimuli (cues) can induce relapse. In order to develop more effective treatment strategies, it is important to understand the neurochemical underpinnings of reinstatement to methamphetamine-seeking behaviors. This proposal will use a combination of behavioral and neurochemical techniques to determine the neurochemical substrates that drive methamphetamine seeking.