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 neuropharmacological 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.? ? Cannabinoid CB1 receptors mediate most central effects of THC, the main psychoactive ingredient in marijuana, particularly effects contributing to abuse liability. Pharmacological manipulation of endocannabinoid system activity by drugs that inhibit transport of endogenous ligands for cannabinoid CB1 receptors into cells where they are degraded or inhibit enzymes responsible for intracellular degradation of endogenous CB1-receptor ligands has been suggested as a safer approach for the treatment of pain and neuropsychiatric disorders than the use of directly-acting cannabinoid CB1-receptor agonists.? ? We have been investigating behavioral and neurochemical effects of the endogenous CB1-receptor ligand anandamide, of inhibitors of fatty acid amide hydrolase (FAAH), the main enzyme responsible for rapid inactivation of anandamide, and of inhibitors of endocannabinoid transport. We previously demonstrated that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also showed that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we previously demonstrated that the reinforcing effects of both anandamide and methanandamide were blocked by pretreatment with the cannabinoid CB1 receptor antagonist rimonabant (SR141716). Thus, converging evidence from our labs suggests the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. We have now evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1 receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward), depending on dose and procedural details. Anandamide (0.03 to 3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamides metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50 to 300 g/kg, intravenous) produced dose-related conditioned place aversions. Development of place aversions with URB597 plus anandamide and with WIN 55,212-2 were prevented by pretreatment with the CB1-receptor antagonist AM251 (3 mg/kg intraperitoneal). When anxiety-related effects of anandamide and URB597 were evaluated in a light-dark box, both anandamide (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. The high 3 mg/kg dose of anandamide produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Thus, additive interactions between the effects of endocannabinoid system activation on brain reward processes and anxiety may account for the aversive effects of high levels of endocannabinoid system activation.? ? Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here we show that homomeric 7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective 7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine (DHBE), 1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, 2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 and 3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens (NAc). Altogether our results indicate that blockade of 7 nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannnabinoids at doses that did not produce depressant or toxic effects, further pointing to 7 nicotinic Ach antagonists as potentially useful agents in the treatment of cannabis abuse in humans.? ? Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis-use disorders. Therefore, we studied intravenous self-administration of 9-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cue-induced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence. ? ? The development of new efficacious medications for the treatment of tobacco dependence is of critical importance and suitable animal models for testing potential medications are needed. Nicotine is the main psychoactive ingredient in tobacco. We previously demonstrated robust reinforcing effects of nicotine in squirrel monkeys under fixed-ratio, fixed-interval and second-order schedules were shown to be mediated by nicotinic receptors, since they could be blocked by pretreatment with the nicotinic antagonist mecamylamine. We have now replicated and extended these findings to progressive-ratio schedules of nicotine self-administration in squirrel monkeys, without the use of any setting conditions such as previous experimental or drug exposure history, and this procedure now allows a clear measure of reinforcing efficacy of nicotine in a non-human primate model that is optimal for preclinical assessment of new anti-smoking medications. These findings provide the clearest demonstration to date that nicotine, by itself and in the absence of other ingredients in tobacco smoke or non-pharmacological stimuli associated with tobacco smoking, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. In these studies, the squirrel monkeys behavior was clearly directed toward self-administration of nicotine and nicotine-seeking was persistent and robust, supporting the use of nicotinic ligands as efficacious approaches to the treatment of tobacco dependence.
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