Basic brain mechanisms underlying drug addiction, cravin

在2004年10月1日至2005年9月30日期间，这一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类药物对脑的作用方面。我们和其他人之前已经报道过，Delta-9-四氢大麻酚(大麻和大麻中具有精神活性和成瘾的成分)增强了对大脑的电刺激奖励，提高了大脑伏隔核中与奖励相关的神经递质多巴胺的细胞外水平，产生了条件性的地点偏好，支持了静脉给药，并在行为上熄灭并通过药物戒毒的实验室动物中触发了寻求药物行为的复发。在本报告所述期间，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寻求可卡因行为的复发，这些实验动物在行为上戒除了以前的可卡因习惯，并在药物上戒毒。此外，我们证实，这种对药物寻找行为的拮抗是由于对神经递质谷氨酸的作用，而不是对预期的神经递质多巴胺的作用。我们进一步发现，AM251显著抑制可卡因增强的脑电刺激奖赏，并显著降低静脉注射可卡因自身给药的累进比率断点。因此，我们认为CB1受体拮抗剂可能作为抗成瘾、抗渴求和抗复发药物用于药物成瘾的临床治疗。我们还提出并发表了一个新的大麻类药物在大脑奖赏和习惯形成底物上作用的机制模型，该模型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。在本报告所述期间，我们还在实验室启动了甲基苯丙胺的研究工作，发现一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(S)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。利用这一新的动物模型，我们发现吸入甲苯在大脑奖赏相关区域的大脑结构和功能上产生了显著的变化。我们还继续研究杏仁核基底外侧复合体在调节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，无论是与可卡因配对还是与吗啡配对的环境线索，都需要杏仁基底外侧核的完整功能，才能获得增强大脑奖励的能力，正如电生理学所测量的那样。我们的发现提出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药物配对环境线索的调节。因此，这些发现与杏仁基底外侧核可能调节导致药物渴望和复发的情绪学习和记忆方面的说法是一致的。本报告所述年度的其他工作更具理论性，侧重于成瘾的实验动物模型及其在抗成瘾、抗渴求和抗复发药物发现中的效用；大脑奖励系统和机制的功能；以及对吸毒行为复发的大脑机制的研究。加上我们以前在这些领域的工作，无论是在数据收集和理论构建方面，我们认为目前的工作促进了对药物成瘾、渴望和复发背后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.