Role of mesopontine cholinergic afferents in methamphetamine reward

药物寻求和奖赏的特征在于腹侧被盖区（VTA）多巴胺（DA）神经元的爆发性放电和中皮质边缘通路内DA释放的增加。其他神经递质，如乙酰胆碱（ACh），在腹侧被盖区起作用，增加多巴胺在一个称为丘脑核（NAc）的通路区域的释放。乙酰胆碱还介导滥用药物的行为强化特征。我们实验室最近发现，甲基苯丙胺（MA）增加ACh和DA在VTA。腹侧被盖区主要接受来自脑桥中脑背侧被盖区的乙酰胆碱连接，激活后可增加多巴胺活性并诱导通路其他区域的释放。因此，LDT胆碱能神经元可能参与MA诱导的DA和ACh增加。此外，VTA内ACh音调可以介导MA寻求行为。 本研究的目的是分离乙酰胆碱投射从LDT的腹侧被盖区，以确定其在神经化学（具体目标1）和行为（具体目标2）的影响MA在小鼠中的重要性。第一个目标将确定参与的LDT ACh连接MA诱导的增加ACh和DA。在这个实验中，我将可逆性地将LDT ACh连接到VTA和使用微透析来测量DA和ACh在小鼠的VTA。我预计LDT ACh的失活将阻止MA诱导的腹侧被盖区ACh和DA的增加。 第二个目标将确定地方发展信托基金对职业培训机构恢复寻求并购的投入。在这个实验中，我将训练小鼠自我管理MA，然后消除这种行为。通常在灭绝后，小剂量的MA引发将恢复MA寻求行为。在给予MA预激剂量之前，我将可逆性阻断LDT ACh连接。我预计这种抑制乙酰胆碱将阻止MA启动恢复药物寻求。 MA成瘾的持续药物寻求特征是通过中皮质边缘通路内广泛的神经化学环境的相互作用来维持的。虽然乙酰胆碱已被发现是至关重要的参与奖励和MA相关的行为，LDT ACh预测的作用，腹侧被盖区在MA寻求行为尚未得到表征。该建议结合了神经化学和行为学方法来定义这种胆碱能投射如何影响腹侧被盖区内的神经化学环境，并最终影响MA寻求。

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.