Persistent Attenuation of Cocaine-Reinforced Behavior

可卡因强化行为的持续减弱

• 批准号: 8413391
• 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/8413391
• 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）： 可卡因的背景增强可卡因的作用是通过从腹侧段落区域（VTA）发射的神经元在伏隔核中释放多巴胺（DA）而产生的。相反，伏隔核中乙酰胆碱（ACH）水平升高可能会抑制食欲行为，包括寻求药物。哺乳动物脑含有两种形式的胆碱酯酶，乙酰胆碱酯酶（ACHE）和丁乙烯酶（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（例如他折断ACH）通过防止ACHE或Buche灭活ACH的突触水平，并可以改善学习和记忆。在动物中，用这些药物的治疗可以减弱可卡因增强的行为。 最近，我们观察到，用某些胆碱酯酶抑制剂（苯乙烯或多奈哌齐，而不是ivastigmine）进行预处理可以产生大鼠可卡因动机行为的持久减少，被描述为持续的衰减（PA）。在杂种大鼠接受10 mg/kg天他的四分之一时，可卡因增强的行为在动物的一半中降低了70％以上，在最后剂量的胆碱酯酶抑制剂（PA阳性大鼠）最后剂量后，这种变化持续了两周或更长时间。可卡因自我给药在其余动物（Pa-negative大鼠）中没有变化。引起PA的他的四方和多奈哌齐与大脑DA水平的升高有关。虽然它可以与他的他的四折或多奈哌齐产生可比的胆碱能迹象，但瑞瓦斯汀的给药不会引起PA，也不会增加海马透析液中的DA。 单独使用MAO（单胺氧化酶）抑制剂进行预处理，可以将可卡因自我给药降低60％以上，但不会引起PA（可卡因自我给药在一个会话中恢复到基线）。这一发现表明，没有胆碱能激活的DA和其他单胺的增加不足以引起PA。进一步的初步研究表明，在可卡因的大鼠中，在可卡因不自我管理的时期，PA不会发生。理由我们的假设是必须组合三个元素以产生PA：1。）伏隔核中ACH受体的激活； 2.）在同一大脑区域激活DA受体； 3.）至少有一些可卡因的一定的自我管理，即使存在低水平。如果是这样，则可以在患者中与临床上可用药物的组合进行预处理后，这些药物激活这些受体，例如Rivastigmine和Bupropion。由于表现出PA的动物中可卡因强化行为的大量减少，可能导致改善药物滥用疾病的药物，这些药物在短期治疗后有效。可卡因增强的持久降低的目的：1。）表征可卡因厌恶性，神经元激活以及ACH，DA和可卡因的水平； 2.）评估da和d2-ligh受体的DA和选择性的作用； 3.）比较对烟碱或毒蕈碱受体有选择性的激动剂的有效性。方法将在多个液体食品增强的时间表和静脉内可卡因的自我管理方面进行训练，以做出反应，并将做出一系列相互排他性的选择，以接收任何一个增强剂。我们将表征可卡因，DA和ACH的大脑浓度在大鼠中表现出可卡因自我给药（PA）的持续减少。可卡因诱导的FOS免疫反应性神经元的激活将在表现出PA或积极自我管理可卡因的大鼠中，对于与增强和厌恶行为相关的大脑区域。还将确定可卡因增强行为长期降低的药物的DA-和ACH受体的选择性。可卡因的厌恶作用将通过允许大鼠对药物或食品增强的相互排他性选择进行评估，并测量其与杠杆的接近性，用于获得钢筋。