Inhibition of monoacylglycerol lipase reduces nicotine withdrawal

Abstract

BACKGROUND AND PURPOSEAbrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored. EXPERIMENTAL APPROACHTo evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets. KEY RESULTSBXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB1 receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans. CONCLUSIONS AND IMPLICATIONSOverall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.

CB 1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal

“…We next studied the consequences of the pharmacological modulation of 2-AG levels in the somatic signs of nicotine abstinence. Interestingly, the administration of the MAGL inhibitor JZL184 decreased the severity of withdrawal, as recently reported (25), while the DAGL inhibitor O7460 exacerbated these symptoms ( Figure 4A). Thus, two-way ANOVA showed an interaction between treatment and pretreatment (F3,50=13.63, p<0.05).…”

“…All drugs were administered in a volume of 10ml per kg of body weight, except for O7460 and JZL184 that were administered in 5ml/kg and 2ml/kg, respectively. Doses of the different drugs used were based on previous studies (22)(23)(24)(25).…”

In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence

“…A well-established and validated nicotine withdrawal model was performed (Bagdas et al, 2014; Damaj et al, 2003; Muldoon et al, 2015; Salas et al, 2007) Mice were infused with 24 mg/kg/day nicotine or saline for 14 days using s.c. osmotic minipumps (model 2000; Alzet Corporation, Cupertino, CA) implanted under isoflurane anesthesia (Jackson et al, 2008). Nicotine concentration was adjusted according to animal weight and mini pump flow rate.…”

Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice

“…Fourteen days after minipump implantation, nicotine withdrawal syndrome was precipitated by the administration of the nicotinic receptor antagonist mecamylamine (2mg/kg). Systemic administration of mecamylamine in nicotine-treated rodents is a wellestablished model to study the neurobiological mechanisms involved in the different aspects that characterize the nicotine withdrawal syndrome (Muldoon et al, 2015;Qi et al, 2015;Parikh et al, 2016;Saravia et al, 2017), typically observed in abstinent smokers.…”