Persistent Attenuation of Cocaine-Reinforced Behavior

描述（由申请人提供）： 背景可卡因的强化作用是通过腹侧被盖区（VTA）投射的神经元释放多巴胺（DA）引起的。相反，丘脑核中乙酰胆碱（ACh）水平的升高可能会抑制食欲行为，包括药物寻求。哺乳动物脑中含有两种形式的胆碱酯酶，乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）。BuChE的生理作用尚不清楚，但它可以代谢可卡因和其他外源性化合物，并有助于ACh的降解。胆碱酯酶抑制剂如他克林通过防止乙酰胆碱酯酶或BuChE失活来增加ACh的突触水平，并且可以改善学习和记忆。在动物中，用这些药物治疗可以减弱可卡因强化的行为。 我们最近观察到，用某些胆碱酯酶抑制剂（他克林或多奈哌齐，但不是rivastigmine）预处理可使大鼠可卡因激发的行为产生持久的减少，称为持续衰减（PA）。在远系繁殖的大鼠接受10毫克/公斤-天的他克林后，可卡因强化的行为在一半的动物中减少了70%以上，这种变化在最后一剂胆碱酯酶抑制剂（PA阳性大鼠）后持续两周或更长时间。其余动物（PA阴性大鼠）的自身给药情况不变。引起PA的他克林和多奈哌齐均与脑DA水平升高相关。虽然其可产生与他克林或多奈哌齐相当的胆碱能体征，但rivastigmine给药不会引起PA，也不会增加海马透析液中的DA。 单独使用单胺氧化酶（MAO）抑制剂进行预处理，可使可卡因自我给药减少60%以上，但不会导致PA（可卡因自我给药在一个疗程内恢复至基线水平）。这一发现表明，增加DA和其他单胺没有胆碱能激活是不足以导致PA。额外的初步研究表明，PA不会发生在可卡因经验的大鼠接受他克林在一段时间内，可卡因是不是自我管理。基本原理我们的假设是，三个要素必须结合起来产生PA：1。激活乙酰胆碱受体在脑桥核; 2.）在同一脑区激活DA受体;和3.）至少有一些偶然的可卡因自我给药，即使水平很低。如果是这样，患者在接受激活这些受体的临床可用药物（如利斯的明和安非他酮）联合治疗前可能会产生PA。由于表现出PA的动物中可卡因强化行为的大量和持久减少，它可能导致改善药物滥用障碍，这些药物在短期治疗后有效。目的为长期减少可卡因强化：1.）表征可卡因厌恶性、神经元活化和ACh、DA和可卡因的水平; 2.）评估DA的作用和对D1和D2样受体的选择性; 3.）比较对烟碱或毒蕈碱受体具有选择性的激动剂的有效性。方法将训练大鼠在液体食物强化和静脉内可卡因自我给药的多重交替时间表下做出反应，并且还将做出一系列相互排斥的选择以接受任何一种药物。我们将描述可卡因，DA和乙酰胆碱在大鼠的大脑浓度，表现出持续减少可卡因自我管理（PA）。可卡因诱导的fos免疫反应性神经元的激活将在表现出PA或主动自我施用可卡因的大鼠中进行比较，用于与强化和厌恶行为相关的大脑区域。DA-和ACh-受体选择性的药物产生长期减少可卡因强化的行为也将被确定。可卡因的厌恶作用将通过允许大鼠对药物或食物强化做出相互排斥的选择并测量它们与用于获得任一种强化剂的杠杆的接近度来评估。

DESCRIPTION (provided by applicant): Background Reinforcing effects of cocaine arise through release of dopamine (DA) in the nucleus accumbens by neurons that project from the ventral tegmental area (VTA). In contrast, elevated levels of acetylcholine (ACh) in the nucleus accumbens may inhibit appetitive behaviors, including drug-seeking. Mammalian brain contains two forms of cholinesterase, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The physiologic role of BuChE is unclear, but it can metabolize cocaine and other exogenous compounds and contributes to degradation of ACh. Cholinesterase inhibitors such as tacrine increase synaptic levels of ACh by preventing its inactivation by AChE or BuChE, and can improve learning and memory. In animals, treatment with these agents can attenuate cocaine-reinforced behavior. We recently observed that pretreatment with certain cholinesterase inhibitors (tacrine or donepezil, but not rivastigmine) can produce long-lasting reductions in cocaine-motivated behavior in rats, described as persistent attenuation (PA). After outbred rats receive 10 mg/kg-day of tacrine, cocaine-reinforced behavior is decreased by more than 70% in one-half of the animals, with this change persisting for two weeks or longer after the last dose of cholinesterase inhibitor (PA-positive rats). Cocaine self-administration is unchanged in the remaining animals (PA-negative rats). Both tacrine and donepezil which cause PA have been associated with increases in brain levels of DA. While it can produce comparable cholinergic signs to tacrine or donepezil, administration of rivastigmine does not cause PA and does not increase DA in hippocampal dialysate. Pretreatment with an MAO (monoamine oxidase) inhibitor alone, can decrease cocaine self-administration by more than 60%, but does not cause PA (cocaine self-administration returns to baseline within one session). This finding shows that an increase in DA and other monoamines without cholinergic activation is not sufficient to cause PA. Additional preliminary studies showed that PA does not occur in cocaine-experienced rats that receive tacrine during a period when cocaine is not self-administered. Rationale Our hypothesis is that three elements must be combined to produce PA: 1.) Activation of ACh receptors in the nucleus accumbens; 2.) Activation of DA receptors in the same brain region; and 3.) At least some contingent self-administration of cocaine, even if present at a low level. If so, PA may be produced in patients after pretreatment with combinations of clinically available agents which activate these receptors, such as rivastigmine and bupropion. Because of the large and long-lasting reductions of cocaine-reinforced behavior in animals exhibiting PA, it may lead to improved medications for substance abuse disorders which are effective after short-term treatment. Aims For long-lasting decreases in cocaine reinforcement: 1.) Characterize cocaine aversiveness, neuronal activation, and levels of ACh, DA, and cocaine; 2.) Assess the role of DA and selectivity for D1- and D2- like receptors; 3.) Compare the effectiveness of agonists that are selective for nicotinic or muscarinic receptors. Methods Rats will be trained to respond under a multiple, alternating schedule of liquid-food reinforcement and self-administration of intravenous cocaine, and will also make a series of mutually-exclusive choices to receive either reinforcer. We will characterize brain concentrations of cocaine, DA, and ACh in rats that exhibit persistent reductions in cocaine self-administration (PA). Cocaine-induced activation of fos-immunoreactive neurons will be compared in rats that either exhibit PA or actively self-administer cocaine, for brain regions associated with reinforced and aversive behaviors. DA- and ACh- receptor selectivity of agents producing long-term reductions in cocaine-reinforced behavior will also be determined. Aversive effects of cocaine will be assessed by allowing rats to make mutually-exclusive choices for drug or food reinforcement and measuring their proximity to levers used to obtain either reinforcer.