Basic brain mechanisms underlying drug addiction, craving, and relapse

药物成瘾、渴望和复发的基本大脑机制

• 批准号: 8553251
• 负责人: Eliot Gardner
• 金额: $ 20.86万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553251
• 关键词: AM630; Addictive Behavior; Agonist; Alcohols; Animal Model; Animals; Area; Attenuated; Beer; Behavior; Behavioral; Behavioral Model; Biochemical; Biological Assay; Biological Models; Blood; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Characteristics; Cocaine; Consumption; Cues; Dependence; Development; Dopamine; Drug Addiction; Economics; Electrical Stimulation of the Brain; Endocannabinoids; Ethanol; Exposure to; Food; Genes; Goals; High Pressure Liquid Chromatography; Hour; Human; Immune system; Immunoblotting; Incentives; Intention; Intravenous; Knowledge; Laboratories; Laboratory Animals; Laboratory Rat; Laboratory mice; Link; Locomotion; Measures; Mediating; Mental Depression; Microdialysis; Microinjections; Modeling; Motivation; Mus; Neuraxis; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Polymerase Chain Reaction; Proteins; Psychological reinforcement; RNA; Receptor Gene; Relapse; Reporting; Research; Resources; Reverse Transcription; Rewards; Sampling; Self Administration; Self-Administered; Stress; Symptoms; Synapses; System; Techniques; Testing; Therapeutic; Time; Western Blotting; Wild Type Mouse; Work; addiction; binge drinking; clinically relevant; craving; discounting; dopamine system; drinking; drinking water; extracellular; in vivo; insight; interest; neurochemistry; novel; pre-clinical; preference; receptor; relating to nervous system; research study

During the present reporting period, our research in this area was limited due to severe reductions in available research resources. Nevertheless, we carried out research in three distinct domains - first, continued research into the existence of cannabinoid CB2 receptors in the brain, second, setting up a reward delay discounting behavioral model in our laboratory, and third, setting up an alcohol binge-drinking behavioral model in our laboratory. In the cannabinoid and endocannabinoid realm of research, the existence of cannabinoid CB2 receptors in the brain has been heretofore controversial. Most evidence has heretofore suggested that only CB1 cannabinoid receptors are found in brain and central nervous system while cannabinoid CB2 receptors are restricted to the body's periphery - primarily in the immune system. However, this view has been challenged by recent claims that CB2 receptors are present in the central nervous system and by recent claims that CB2 receptors modulate synaptic activity. Therefore, we used highly selective CB2 agonists and antagonists, combined with the use of CB1 and CB2 receptor gene-deleted mice, to study CB2 involvement in cocaine's behavioral and neurochemical effects. We found that the CB2 receptor-selective agonist JWH133 attenuates intravenous cocaine self-administration in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. This effect was abolished by the CB2 receptor-selective antagonist AM630. To confirm our findings, we also used the CB2-selective agonist GW405833 and found a similar inhibition of intravenous cocaine self-administration in wild-type mice. Under progressive-ratio reinforcement conditions, we found that JWH133 inhibits incentive motivation to self-administer cocaine, as evidenced by strong reductions in the progressive-ratio break-point. Similar effects were found when JWH133 was administered intra-nasally (for direct passage into the brain via the cribiform plate) or administered by direct intracerebral microinjections of JWH133 into the nucleus accumbens. Again, the effect was seen in wild-type but not in CB2 receptor gene-deleted mice. JWH133 by itself was found to have no reinforcing or aversive effects, as assessed by intravenous self-administration and by conditioned place preference/aversion experiments. Further, JWH133 inhibited cocaine-enhanced locomotion in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. JWH133 by itself had an inhibitory effect on locmotion, both with systemic administration and with intracerebral microinjection into the nucleus accumbens in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. The CB2 selective antagonist AM630 had a stimulatory effect on locomotion, both with systemic administration and with intracerebral microinjection into the nucleus accumbens in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. JWH133 by itself inhibited extracellular nucleus accumbens dopamine as measured by real-time in vivo brain microdialysis. JWH133 also inbited basal and cocaine-enhanced extracellular nucleus accumbens dopamine as measured by real-time in vivo brain microdialysis. This effect was blocked by the CB2-selective antagonist AM630. By itself, AM630 - microinjected intracerebrally into the nucleus accumbens - aumented basal extracellular nucleus accumbens dopamine. We conclude that CB2 cannabinoid receptors exist in the brain, that CB2 receptors functionally modulate the meso-accumbens dopamine system, that CB2 receptors functionally modulate dopamine-mediated behaviors, and that the brain CB1 and Cb2 receptor-linked neural systems may functionally antagonize each other in a reciprocal mutually antatagonistic manner. Such mechanistic knowledge can aid in the search for new and effective pharmacotherapeutic compounds for the treatment of drug addiction and dependence. In addition, during this reporting period, we introduced a reward-delay-discounting animal model into our battery of preclinical animal models of addiction. At the human level, inability to delay gratification is a pathognomonic symptom of drug addiction. Therefore, we added the reward-delay-discounting task to our battery of preclinical animal models. In this task, laboratory rats are presented with two wall-mounted levers in their test chambers. Depression of one lever delivers a food reward immediately. Depression of the other lever delivers a larger reward after a delay period ranging up to 60 seconds. The animal must choose whether it desires a small immediate reward or a larger delayed reward. In this manner, impulsive choice can be measured and quantified. It is our intention to use this new animal model to measure the effect of addictive drugs on impulsive choice, and also to determine whether any of our putative anti-addiction pharmacotherapies can change addictive-drug-altered impulsice choice in a putatively therapeutic direction. We believe that the addition of this new model - derived from behavioral economics - gives us an entirely new clinically-relevant perspective to evaluate potentially therapeutic anti-addiction anti-craving anti-relapse medications at the preclinical animal model level. In addition, during this reporting period, we introduced an alcohol binge-drinking animal model into our battery of preclinical animal models of addiction. At the human level, binge-type drug taking behavior is often characteristic of drug addiction. Therefore, we have added an alcohol binge-drinking animal model. In this task, laboratory mice are allowed to drink water, near beer (containing no ethanol), or beer (containing 2% ethanol) for 2 hours per day. Binge drinking is operationally defined as bringing blood ethanol levels up to at least 80mg/dl within 2 hours of the initial drink. It is our intention to use this new animal model to determine whether any of our putative anti-addiction pharmacotherapies can alter binge drinking in a putatively therapeutic direction. We believe that the addition of this new model gives us yet another new clinically-relevant perspective to evaluate potentially therapeutic anti-addiction anti-craving anti-relapse medications at the preclinical animal model level. If successful, we intend to investigate binge consumption of other addictive drugs.

在本报告期间，由于可用的研究资源严重减少，我们在该领域的研究受到限制。 然而，我们在三个不同的领域进行了研究 - 首先，对大脑中大麻素CB2受体的存在的持续研究，其次，在我们的实验室中建立了奖励延迟折现行为模型，第三，在我们的实验室中建立了酒精暴饮暴食的行为模型。 在研究的大麻素和内源性大麻素领域中，大脑中大麻素CB2受体的存在引起了争议。 迄今为止，大多数证据表明，在大脑和中枢神经系统中只发现CB1大麻素受体，而大麻素CB2受体仅限于人体的周围 - 主要在免疫系统中。 但是，最近的说法挑战了这种观点，即中枢神经系统中存在CB2受体，并且最近声称CB2受体调节突触活动。 因此，我们使用高度选择性的CB2激动剂和拮抗剂，结合使用CB1和CB2受体基因删除小鼠，研究CB2参与可卡因的行为和神经化学作用。 我们发现，CB2受体选择性激动剂JWH133减弱了野生型和CB1基因剥落小鼠中可卡因自我给药，但在CB2基因删除的小鼠中却没有。 CB2受体选择性拮抗剂AM630废除了这种效果。 为了确认我们的发现，我们还使用了CB2选择性激动剂GW405833，并发现在野生型小鼠中对可卡因自我给药的抑制类似。 在渐进率的增强条件下，我们发现JWH133抑制了自我管理可卡因的激励动机，这证明了渐进式利益突破点的强劲降低。 当JWH133被纳入神经内（用于通过婴儿型板直接传递到大脑）或通过直接脑内显微注射jWH133施用JWH133时，也发现了类似的效果。 同样，这种作用在野生型中观察到，但在CB2受体基因删除的小鼠中没有看到。 通过静脉自我给药和条件的位置偏好/厌恶实验，发现JWH133本身没有增强或厌恶作用。 此外，JWH133抑制了野生型和CB1基因删除的小鼠中可卡因增强的运动，但在CB2基因删除的小鼠中却没有。 JWH133本身对LocMotion具有抑制作用，无论是全身给药，并且在野生型和CB1基因删除的小鼠中对伏隔核的脑静脉显微注射，但在CB2基因删除的小鼠中却没有。 CB2选择性拮抗剂AM630对野生型和CB1基因剥落的小鼠的运动和脑内显微注射均具有刺激作用，并且在CB2基因上含量的小鼠中均具有脑脑中的显微注射。 JWH133本身抑制了通过体内脑微透析实时测量的细胞外伏伏胺多巴胺。 JWH133还通过实时的体内脑微透析测量了基底和可卡因增强的细胞外核多巴胺。 CB2选择性拮抗剂AM630阻止了这种效果。 本身，AM630-微型注射在伏隔核中 - 尤其是尤其的基础细胞外核伏托胺多巴胺。 我们得出的结论是，CB2大麻素受体存在于大脑中，CB2受体在功能上调节了中氧化胺的多巴胺系统，CB2受体在功能上调节多巴胺介导的行为，并且脑CB1和CB2受体链接的神经系统可以在互惠式蚂蚁中互相促进脑部的脑部相互作用。 这种机械知识可以帮助寻找新的有效的药物治疗化合物，以治疗药物成瘾和依赖性。 此外，在此报告期间，我们在临床前动物的成瘾模型中引入了奖励延迟订阅动物模型。 在人类一级，无法延迟满足是药物成瘾的病理性症状。 因此，我们在临床前动物模型的电池中添加了奖励延迟订票任务。 在这项任务中，实验室大鼠的测试室中有两个壁挂式杠杆。 一个杠杆的凹陷立即提供食物奖励。 另一个杠杆的凹陷在延迟期内可提供更大的奖励，范围为60秒。 动物必须选择需要立即奖励或更大的延迟奖励。 以这种方式，可以测量和量化冲动的选择。 我们的意图是使用这种新动物模型来衡量成瘾性药物对冲动性选择的影响，并确定我们推定的抗瘾药物治疗是否可以在推定的治疗方向上改变成瘾性的毒品改变的冲动选择。 我们认为，这种新模型的添加（源自行为经济学）为我们提供了一个全新的临床上与临床相关的观点，可以评估在临时性动物模型水平上的潜在治疗性抗增加抗避免抗狂欢的抗雷神药物。 此外，在此报告期间，我们将饮酒的动物模型引入了我们成瘾的临床前动物模型中。 在人类一级，暴饮暴食型服用行为通常是药物成瘾的特征。 因此，我们添加了酒精暴饮暴食的动物模型。 在这项任务中，允许实验室小鼠每天喝水（无乙醇）或啤酒（含2％乙醇）每天2小时。 暴饮暴食在操作上定义为在初次饮料的2小时内将血液乙醇水平至少达到80mg/dl。 我们的意图是使用这种新动物模型来确定我们推定的抗添加药物治疗是否可以沿推定的治疗方向改变暴饮暴食。 我们认为，这种新模型的添加为我们提供了另一个与临床相关的新观点，以评估临床前动物模型水平上潜在的治疗性抗毒性抗避免抗狂物药物。 如果成功，我们打算调查其他成瘾药物的暴饮暴食。