Persistent Attenuation of Cocaine-Reinforced Behavior

可卡因强化行为的持续减弱

• 批准号: 8598009
• 负责人: KENNETH W. GRASING
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598009
• 关键词: Acetylcholine; Acetylcholinesterase; Addictive Behavior; Address; Aftercare; Agonist; Animals; Anterior; Appetitive Behavior; Attenuated; Behavior; Boxing; Brain; Brain region; Bupropion; Butyrylcholinesterase; Cholinergic Receptors; Cholinesterase Inhibitors; Cholinesterases; Cocaine; Cocaine Abuse; Cocaine Dependence; Disease; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Drug Addiction; Drug toxicity; Elements; Exhibits; FOS gene; Food; Health; Hippocampus (Brain); Individual; Intravenous; Lead; Learning; Liquid substance; Location; Measures; Mediating; Medical; Memory; Metabolism; Methods; Monoamine Oxidase Inhibitors; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinic M1 Receptor; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Physiological; Property; Psychological reinforcement; Rattus; Role; Schedule; Self Administration; Self-Administered; Series; Signal Transduction; Study Section; Substance abuse problem; Synapses; Tacrine; Testing; Training; Ventral Tegmental Area; Veterans; attenuation; cholinergic; compare effectiveness; disorder later incidence prevention; donepezil; drug abuse prevention; drug reinforcement; experience; immunoreactivity; improved; medication compliance; meetings; monoamine; motivated behavior; novel; prevent; receptor; reinforced behavior; reinforcer; reuptake; rivastigmine; social; substance abuse treatment; transmission process

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.

描述(由申请人提供)： 背景可卡因的增强作用是通过腹侧被盖区(VTA)投射的神经元释放伏核中的多巴胺(DA)来实现的。相比之下，伏隔核中乙酰胆碱(ACh)水平的升高可能会抑制食欲行为，包括寻求药物。哺乳动物的大脑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AChE或BuChE使ACh失活，增加了ACh的突触水平，并可以改善学习和记忆。在动物身上，这些药物的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，但不是利瓦斯汀)预处理可以在大鼠的可卡因动机行为中产生持久的减少，称为持续性衰减(PA)。在杂交大鼠每天服用10 mg/kg他克林后，一半动物的可卡因增强行为减少了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)的可卡因自身给药情况不变。导致PA的他克林和多奈哌齐都与大脑DA水平的增加有关。虽然它可以产生类似于他克林或多奈哌齐的胆碱能体征，但给予利瓦斯汀不会引起PA，也不会增加海马透析液中的DA。单独使用单胺氧化酶(MAO)抑制剂可以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次会议内恢复到基线)。这一发现表明，在没有胆碱能激活的情况下，DA和其他单胺的增加不足以引起PA。另外的初步研究表明，在可卡因非自我给药期间接受他克林治疗的可卡因经验丰富的大鼠中不会出现PA。我们的假设的基本原理是，必须将三个要素结合起来才能产生PA：1。伏隔核内ACh受体的激活；同一脑区DA受体的激活；至少有一些或有可能自行注射可卡因，即使是低水平的可卡因。如果是这样的话，患者在用临床上可用的激活这些受体的药物组合，如利瓦斯汀和安非他酮进行预处理后，可能会产生PA。由于表现出PA的动物可卡因强化行为的大幅和持久的减少，这可能导致改善药物滥用障碍的药物，这些药物在短期治疗后是有效的。旨在长期减少可卡因强化：1.)描述可卡因的厌恶、神经元激活以及ACh、DA和可卡因的水平；评估DA的作用以及对D1样和D2样受体的选择性；比较对烟碱或毒扁豆碱受体有选择性的激动剂的有效性。方法训练大鼠在液体食物强化和自身静脉注射可卡因的多重交替程序下做出反应，并进行一系列相互排斥的选择以接受任何一种强化剂。我们将描述可卡因自我给药(PA)持续减少的大鼠脑内可卡因、DA和ACh的浓度。可卡因诱导的FOS免疫反应神经元的激活将在表现为PA或主动自我注射可卡因的大鼠中进行比较，以寻找与强化和厌恶行为相关的大脑区域。还将确定在可卡因强化行为中产生长期减少的药物的DA和ACh受体选择性。可卡因的厌恶效应将通过允许老鼠为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何一种增强剂的杠杆的接近程度来评估。