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: 8336450
• 负责人: Eliot Gardner
• 金额: $ 20.81万
• 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/8336450
• 关键词: AM630; Addictive Behavior; Adverse effects; Agonist; Animal Model; Animals; Antismoking; Area; Attenuated; Behavior; Behavioral; Behavioral Model; Biochemical; Biological Assay; Biological Models; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Chronic; Cocaine; Cues; Dependence; Development; Dopamine; Drug Addiction; Economics; Electrical Stimulation of the Brain; Endocannabinoids; Exposure to; Food; Future; Genes; Goals; High Pressure Liquid Chromatography; Human; Immune system; Immunoblotting; Incentives; Intention; Intravenous; Knowledge; Laboratories; Laboratory Animals; Laboratory Rat; Link; Locomotion; Measures; Mediating; Mental Depression; Microdialysis; Microinjections; Modeling; Motivation; Mus; Neuraxis; Nicotine; Nicotine Dependence; Nicotinic Agonists; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Polymerase Chain Reaction; Property; 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; Therapeutic Effect; Time; Treatment Efficacy; Western Blotting; Wild Type Mouse; Work; addiction; clinically relevant; craving; design; discounting; dopamine system; extracellular; follow-up; in vivo; insight; interest; neurochemistry; novel; pre-clinical; preference; receptor; relating to nervous system; research study; smoking cessation; varenicline

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 basic brain mechanisms of action of the anti-nicotine smoking-cessation medication varenicline, second, research into the existence of cannabinoid CB2 receptors in the brain, and third, setting up a reward delay discounting behavioral model in our labortory. Our verenicline work during the present reporting period was a follow-up to our extensive previous research on varenicline in which we proved that varenicline's alpha4beta2 nicotinic partial agonist properties are essential to its therapeutic effect on smoking cessation while its alpha7 nicotinic agonist properties are irrelevant to its therapeutic action. Thus, future anti-nicotine-addiction anti-smoking pharmacotherapies can be designed with only alpha4beta2 nicotinic partial agonist properties - thus enhancing therapeutic efficacy and diminishing the liklihood of producing unwanted side effects. 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 additiom, during this reporting period, we introduced a new 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 have introduced a reward delay discounting task into our laboratory. 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 chronic administration 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.

在本报告所述期间，由于可用研究资源严重减少，我们在这一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，继续研究抗尼古丁戒烟药物varenicline的基本大脑作用机制，第二，研究大脑中大麻素CB 2受体的存在，第三，在我们的实验室建立奖励延迟折扣行为模型。 我们在本报告期内的维伦克林工作是对我们先前关于维伦克林的广泛研究的后续，在该研究中，我们证明了维伦克林的α 4 β 2烟碱部分激动剂特性对其戒烟治疗效果至关重要，而其α 7烟碱激动剂特性与其治疗作用无关。 因此，未来的抗尼古丁成瘾、抗吸烟药物疗法可以设计成仅具有α 4 β 2烟碱部分激动剂性质，从而增强治疗功效并减少产生不希望的副作用的可能性。 在大麻素和内源性大麻素的研究领域，大麻素CB 2受体在大脑中的存在迄今为止一直存在争议。 迄今为止，大多数证据表明，只有CB 1大麻素受体存在于大脑和中枢神经系统中，而大麻素CB 2受体仅限于身体的外周-主要是免疫系统。 然而，这一观点受到了挑战，最近的索赔，CB 2受体存在于中枢神经系统和最近的索赔，CB 2受体调节突触活动。 因此，我们使用高选择性的CB 2激动剂和拮抗剂，结合使用CB 1和CB 2受体基因缺失的小鼠，研究CB 2参与可卡因的行为和神经化学作用。 我们发现CB 2受体选择性激动剂JWH 133减弱了野生型和CB 1基因缺失小鼠的静脉内可卡因自我给药，但在CB 2基因缺失小鼠中没有。 CB 2受体选择性拮抗剂AM 630可消除这种作用。 为了证实我们的发现，我们还使用了CB 2选择性激动剂GW 405833，并发现野生型小鼠静脉内可卡因自我给药的类似抑制作用。 在累进比强化条件下，我们发现JWH 133抑制自我管理可卡因的激励动机，累进比断点的强烈减少证明了这一点。 当JWH 133鼻内给药（通过筛板直接进入大脑）或通过将JWH 133直接脑内显微注射到脑桥核中给药时，发现了类似的效果。 同样，在野生型小鼠中观察到了这种效应，但在CB 2受体基因缺失的小鼠中没有观察到这种效应。 通过静脉内自我给药和条件性位置偏好/厌恶实验评估，发现JWH 133本身没有增强或厌恶作用。 此外，JWH 133抑制可卡因增强的运动在野生型和CB 1基因缺失的小鼠，但不在CB 2基因缺失的小鼠。 JWH 133本身对locmotion有抑制作用，无论是在野生型和CB 1基因缺失小鼠中全身给药还是脑内微注射到脑桥核中，但在CB 2基因缺失小鼠中没有。 CB 2选择性拮抗剂AM 630对运动有刺激作用，无论是全身给药还是脑内微量注射到野生型和CB 1基因缺失小鼠的丘脑核中，但在CB 2基因缺失小鼠中没有。 通过实时体内脑微透析测量，JWH 133本身抑制细胞外核多巴胺。 JWH 133还抑制基础和可卡因增强的细胞外核多巴胺，如通过实时体内脑微透析测量的。 这种作用被CB 2选择性拮抗剂AM 630阻断。 单独地，将AM 630-微注射到基底细胞外核中，使多巴胺分泌。 我们的结论是，CB 2大麻素受体存在于大脑中，CB 2受体功能调节中-多巴胺系统，CB 2受体功能调节多巴胺介导的行为，和大脑CB 1和CB 2受体相关的神经系统可能在功能上相互拮抗，相互拮抗的方式。 这种机制知识可以帮助寻找新的和有效的药物化合物用于治疗药物成瘾和依赖。 此外，在本报告期内，我们将一种新的动物模型引入到我们的成瘾临床前动物模型组合中。 在人类的层面上，无法延迟满足是药物成瘾的一种特征性症状。 因此，我们在实验室中引入了奖励延迟折扣任务。 在这项任务中，实验室大鼠在其测试室中有两个壁挂式杠杆。 按下一个杠杆立即提供食物奖励。 按下另一个杠杆会在延迟60秒后提供更大的奖励。 动物必须选择它是否想要一个小的立即奖励或更大的延迟奖励。 通过这种方式，冲动的选择可以被测量和量化。 我们的目的是使用这种新的动物模型来测量成瘾药物的长期给药对冲动选择的影响，并确定我们假定的抗成瘾药物疗法是否可以改变成瘾药物改变的冲动选择。 我们相信，这种新模型的加入-来自行为经济学-为我们提供了一个全新的临床相关视角，以在临床前动物模型水平上评估潜在的治疗性抗成瘾、抗渴望、抗复发药物。