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从腹侧被盖区（VTA）投射的神经元在伏核中释放多巴胺（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（例如他克林）可通过防止乙酰胆碱酯酶 (AChE) 或丁胆碱酯酶 (BuChE) 失活来增加乙酰胆碱 (ACh) 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，但不是卡巴拉汀）进行预处理可以使大鼠的可卡因诱发行为产生持久的减少，称为持续衰减（PA）。近交系大鼠接受每天 10 毫克/公斤的他克林后，一半动物的可卡因强化行为减少了 70% 以上，这种变化在最后一次服用胆碱酯酶抑制剂（PA 阳性大鼠）后持续两周或更长时间。可卡因自我给药在其余动物（PA 阴性大鼠）中没有变化。引起 PA 的他克林和多奈哌齐都与脑内 DA 水平的增加有关。虽然卡巴拉汀可产生与他克林或多奈哌齐类似的胆碱能症状，但卡巴拉汀不会引起 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，可将可卡因自我给药量减少 60% 以上，但不会引起 PA（可卡因自我给药量在一次疗程内恢复到基线）。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。其他初步研究表明，在未自行服用可卡因期间接受他克林的有过可卡因经历的大鼠中不会发生 PA。基本原理 我们的假设是，必须结合三个要素才能产生 PA： 1.) 伏隔核中 ACh 受体的激活； 2.) 激活同一大脑区域的 DA 受体； 3.) 至少偶尔自行服用可卡因，即使剂量较低。如果是这样，患者在使用激活这些受体的临床可用药物（例如卡巴拉汀和安非他酮）进行预处理后，可能会产生 PA。由于表现出 PA 的动物的可卡因强化行为大幅且持久地减少，因此可能会导致药物滥用疾病药物的改进，这些药物在短期治疗后有效。目标 长期减少可卡因强化： 1.) 表征可卡因厌恶、神经元激活以及 ACh、DA 和可卡因水平； 2.) 评估 DA 的作用以及对 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 训练大鼠在多种、交替的液体食物强化和静脉注射可卡因的自我给药方案下做出反应，并且还将做出一系列相互排斥的选择来接受任一强化剂。我们将描述可卡因自我给药 (PA) 持续减少的大鼠大脑中可卡因、DA 和 ACh 的浓度。将在表现出 PA 或主动自我施用可卡因的大鼠中比较可卡因诱导的 fos 免疫反应性神经元的激活，以了解与强化和厌恶行为相关的大脑区域。还将确定能够长期减少可卡因强化行为的药物的 DA 和 ACh 受体选择性。可卡因的厌恶作用将通过让老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强化剂的杠杆的接近程度来评估。