Basic brain mechanisms underlying drug addiction, cravin

在2004年10月1日至2005年9月30日期间，该研究项目取得了重大进展，特别是在内源性大麻素脑机制和大麻素药物对脑的作用方面。我们和其他人之前曾报道过-9-四氢大麻酚（大麻和大麻中具有精神活性和成瘾性的成分）增强脑电刺激奖励，增强大脑中与奖励相关的伏隔核中神经递质多巴胺的细胞外水平，产生条件偏好，支持静脉注射药物自我给药，并在实验动物中引发寻求药物行为的复发，这些动物的行为已经消失，并且从药理学上从以前的吸毒习惯中解脱出来。在本报告期间，我们发现并报告了大麻素CB1受体拮抗剂AM251显著抑制可卡因引发的可卡因寻求行为的复发，实验动物行为消失并从药理学上解毒以前的可卡因吸食习惯。此外，我们确定这种药物寻找行为的拮抗作用是由于对神经递质谷氨酸的作用，而不是预期的神经递质多巴胺。我们进一步发现，AM251显著抑制可卡因增强的脑电刺激奖励，并显著降低静脉注射可卡因自我给药的渐进比断点。基于这些理由，我们建议CB1受体拮抗剂可能在临床上作为抗成瘾，抗渴望和抗复发药物治疗药物成瘾有用。我们还提出并发表了大麻素作用于大脑中奖励和习惯形成基质的新机制模型，这可能有助于解释大麻成瘾，也可能为大麻成瘾提供新的治疗方法。在报告期内，我们还在实验室开展了甲基苯丙胺的研究工作，发现单次注射甲基苯丙胺可显著减弱可卡因的行为和神经化学作用。甲基苯丙胺在这方面的作用机制尚不清楚，可能是甲基苯丙胺神经毒性的反映。此外，在本报告所述期间，我们与布鲁克海文国家实验室的研究同事合作开发了一种吸入剂滥用的动物模型。使用这种新的动物模型，我们发现吸入甲苯对脑结构和脑奖励相关位点的功能产生了显著的变化。我们还继续研究了杏仁核基底外侧复合体在介导成瘾药物配对线索诱导的脑电刺激奖励增强中的作用。我们发现，通过电生理学测量，可卡因和吗啡配对的环境线索都需要基底外侧杏仁核的完整功能来获得增强大脑奖励的能力。我们的发现表明了一种巴甫洛夫条件反射现象，在这种现象中，大脑奖励回路的功能受到与药物配对的环境线索的调节。因此，这些发现与基底外侧杏仁核可能介导导致药物渴望和复发的情绪学习和记忆方面的建议一致。在报告年度的其他工作，更多的是理论性的，侧重于成瘾的实验动物模型及其在抗成瘾，抗渴望和抗复发药物发现中的应用；论脑奖励系统和机制的功能以及药物寻求行为复发的大脑机制。结合我们之前在这些领域的工作，无论是在数据收集方面还是在理论构建方面，我们相信目前的工作促进了对药物成瘾、渴望和复发的基本大脑机制的理解。

During the period 01 Oct 04 to 30 Sept 05, significant progress was made on this research project, most especially in the area of endocannabinoid brain mechanisms and cannabinoid drug action on the brain. We and others had previously reported that delta-9-tetrahydrocannabinol (the psychoactive and addictive constituent in marijuana and hashish) enhances electrical brain-stimulation reward, enhances extracellular levels of the neurotransmitter dopamine in the reward-related nucleus accumbens of the brain, produces conditioned place preferences, supports intravenous drug self-administration, and triggers relapse to drug-seeking behavior in laboratory animals behaviorally extinguished and pharmacologically detoxified from their prior drug-taking habits. During the present reporting period, we found and reported that the cannabinoid CB1 receptor antagonist AM251 significantly inhibits cocaine-triggered relapse to cocaine-seeking behavior in laboratory animals behaviorally extinguished and pharmacologically detoxified from their prior cocaine-taking habits. Furthermore, we established that this antagonism of drug-seeking behavior is due to action on the neurotransmitter glutamate, rather than the expected neurotransmitter dopamine. We further found that AM251 significantly inhibits cocaine-enhanced electrical brain-stimulation reward, and significantly lowers the progressive-ratio break-point for intravenous cocaine self-administration. On these grounds, we suggest that CB1 receptor antagonists may be clinically useful as anti-addiction, anti-craving, and anti-relapse medications for the treatment of drug addiction. We also proposed and published a new mechanistic model for cannabinoid actions on reward and habit-formation substrates in the brain, that may help to explain marijuana addiction and may also suggest new treatment approaches for marijuana addiction. During the reporting period, we also initiated work on methamphetamine in our laboratory, and found that a single injection of methamphetamine significantly attenuates cocaine's behavioral and neurochemical actions. The mechanism(s) of methamphetamine's actions in this regard are as yet unknown, and may be a reflection of methamphetamine neurotoxicity. In addition, during this reporting period we developed - in collaboration with our research colleagues at Brookhaven National Laboratory - an animal model of inhalant abuse. Using this new animal model, we found that toluene inhalation produced significant changes in brain structure and function in brain reward-related loci. We also continued our work on the role of the basolateral complex of the amygdala in mediating addictive-drug-paired cue-induced enhancement of electrical brain-stimulation reward. We found that intact functioning of the basolateral amygdala is needed for both cocaine-paired and morphine-paired environmental cues to acquire the ability to enhance brain reward, as measured electrophysiologically. Our findings suggest a Pavlovian conditioning phenomenon in which the functioning of brain-reward circuitry is modulated by drug-paired environmental cues. As such, these findings are in agreement with suggestions that the basolateral amygdala may mediate aspects of emotional learning and memory that contribute to drug craving and relapse. Other work during the reporting year, more theoretical in nature, focused on laboratory animal models of addiction and their utility in anti-addiction, anti-craving, and anti-relapse medication discovery; on the functioning of brain-reward systems and mechanisms; and on brain mechanisms of relapse to drug-seeking behavior. When added to our previous work in these areas, both in terms of data-gathering and theory-building, we believe that the present work advances understanding of the basic brain mechanisms underlying drug addiction, craving, and relapse.