Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neurobiological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Tobacco dependence is the leading preventable cause of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors reduces or eliminates many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of the natural cannabinoid delta-9-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preferences when given together. These previous studies have used systemically administered CB1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit the uptake of of the endocannabinoid anandamide into cells where it is degraded by fatty acid amide hydrolase (FAAH), or to inhibit the activity of FAAH,thereby magnifying and prolonging the effects of the endogenous anandamide only when and where it is synthesized and released on demand. We have evaluated whether the FAAH inhibitor URB597 could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. We also evaluated the effects of the anandamide uptake inhibitor AM404 which also prevented development of nicotine-induced CPP and reduced nicotine-induced reinstatement in the CPP model of relapse. Parallel in vivo electrophysiology experiments showed that URB597 blocked the activation of dopamine neurons in the ventral tegmental area by nicotine and in vivo microdialysis experiments showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the two main areas of the brain's mesolimbic reward system. These findings suggest that anandamide uptake inhibition or FAAH inhibition can counteract the addictive properties of nicotine and that such inhibitors are potential medications for treatment of tobacco dependence. The effects of cannabinoid CB1 receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement and on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the cannabinoid CB1receptor antagonist rimonabant, but not by the CB2 receptor antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1 receptor signalling might have therapeutic value for treating tobacco dependence. Two endogenous ligands for cannabinoid CB1 receptors, anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol(2-AG), have been identified and characterized. 2-AG is the most prevalent endogenous cannabinoid ligand in the brain, and electrophysiological studies suggest 2-AG, rather than anandamide, is the true natural ligand for cannabinoid receptors and the key endocannabinoid involved in retrograde signaling in the brain. We have evaluated intravenously administered 2-AG for reinforcing effects in experimental animals. Subjects that previously self-administered anandamide or nicotine under a fixed-ratio schedule had their self-administration behavior extinguished by vehicle substitution and were then given the opportunity to self-administer 2-AG. Intravenous 2-AG was a very effective reinforcer of drug-taking behavior, maintaining higher numbers of self-administered injections per session and higher rates of responding than vehicle across a wide range of doses. To assess involvement of CB1 receptors in the reinforcing effects of 2-AG, we pretreated subjects with the cannabinoid CB1 antagonist rimonabant. Rimonabant produced persistent blockade of 2-AG self-administration without affecting responding maintained by food under similar conditions. Thus, 2-AG was actively self-administered in subjects with or without a history of cannabinoid self-administration,and the reinforcing effects of 2-AG were mediated by CB1 receptors. Self-administration of 2-AG by experimental animals provides a valuable procedure for studying abuse liability of medications that interfere with 2-AG signaling within the brain and for investigating mechanisms involved in the reinforcing effects of endocannabinoids. Nicotine stimulates the activity of mesolimbic dopamine neurons, and this is believed to mediate the rewarding and addictive properties of tobacco use. We have investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area of rats with electrophysiological techniques both in vivo and in vitro. We discovered that pharmacological inhibition of FAAH suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of anandamide. OEA and PEA are naturally occurring lipid signaling molecules structurally related to anandamide, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor- alpha (PPAR alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. These data indicate that PPAR alpha agonists, which are used clinically for treatment of lipid disorders, might have therapeutic value for treating tobacco dependence.
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