anandamide and Tobacco-Use-Disorder

Nicotine in tobacco, tetrahydrocannabinol (delta 9-THC) in marijuana and morphine in opium are well known as drugs associated with dependence or addiction. Endogenous active substances that mimic the effects of the natural drugs and their respective receptors have been found in the mammalian central nervous system (CNS). Such active substances and receptors include acetylcholine (ACh) and the nicotinic ACh receptor (nAChR) for nicotine, anandamide and CB1 for delta 9-THC, and endomorphins (1 and 2) and the mu (OP3) opioid receptor for morphine, respectively. Considerable progress has been made in studies on neurotoxicity, in terms of the habituation, dependence and withdrawal phenomena associated with these drugs and with respect to correlations with endogenous active substances and their receptors. In this article we shall review recent findings related to the neurotoxicity of tobacco, marijuana and opium, and their toxic ingredients, nicotine, delta 9-THC and morphine in relation to their respective endogenous agents and receptors in the CNS.

Topics: Acetylcholine; Arachidonic Acids; Brain Chemistry; Cannabis; Dronabinol; Endocannabinoids; Endorphins; Humans; Marijuana Abuse; Morphine; Morphine Dependence; Nicotine; Opium; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Receptors, Nicotinic; Receptors, Opioid; Tobacco Use Disorder

The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB1 and CB2 receptors, CB1Rs and CB2Rs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CB1R and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown.. The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CB1R, CB2R, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats.. URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CB1R antagonist rimonabant, but not by the CB2R or PPARα antagonists AM630 and MK886, respectively.. These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB1 receptor-dependent mechanism, and not via CB2R or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Antagonists; Carbamates; Cues; Drug-Seeking Behavior; Endocannabinoids; Male; Nicotine; Piperidines; Polyunsaturated Alkamides; PPAR alpha; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Tobacco Use Disorder

The endocannabinoid system appears to play a pivotal role in mediating the rewarding and reinforcing effects of nicotine. Recent studies have shown that the inhibition of fatty acid amide hydrolase (FAAH) attenuates reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues. FAAH hydrolyses the endogenous endocannabinoid anandamide, as well as other non-cannabinoid ligands such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). As OEA and PEA can attenuate both nicotine-taking and nicotine-seeking behaviour, the specific role of anandamide remains unclear. In this study, we have tested the selective anadamide uptake inhibitor, VDM11, which elevates anandamide levels without affecting levels of OEA/PEA, on nicotine-taking and nicotine-seeking behaviour.. We used a nicotine intravenous self-administration model in rats to assess the effect of VDM11, given i.p., on nicotine taking using fixed and progressive ratio schedules of reinforcement as well as on reinstatement of nicotine-seeking induced by nicotine priming and nicotine-associated cues.. VDM11 did not affect levels of responding for nicotine under fixed-ratio and progressive-ratio schedules of reinforcement. In contrast, VDM11 dose-dependently attenuated reinstatement of nicotine-seeking behaviour induced by nicotine-associated cues and nicotine priming.. These results indicate that ligands elevating anandamide levels could have therapeutic value for preventing relapse into nicotine-seeking behaviour and should be tested in humans trying to quit smoking.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Conditioning, Operant; Drug-Seeking Behavior; Endocannabinoids; Extinction, Psychological; Male; Nicotine; Polyunsaturated Alkamides; Rats; Rats, Long-Evans; Reinforcement Schedule; Self Administration; Tobacco Use Disorder

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 CB(1) receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Delta(9)-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB(1) receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB(1) receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) 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. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Carbamates; Conditioning, Psychological; Dopamine; Endocannabinoids; Hydrolysis; Male; Motor Activity; Nicotine; Nucleus Accumbens; Polyunsaturated Alkamides; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Reward; Self Administration; Tobacco Use Disorder