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.
