title: Inhibition of monoacylglycerol lipase reduces nicotine withdrawal.
abstract: OBJECTIVE
  Abrupt 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  BXD 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
  Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Muldoon
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: J L
authors.initials: JL
authors.lastname: Harenza
authors.forename: R A
authors.initials: RA
authors.lastname: Abdullah
authors.forename: L J
authors.initials: LJ
authors.lastname: Sim-Selley
authors.forename: B F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: M F
authors.initials: MF
authors.lastname: Miles
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: A H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: M I
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
chemical_list: D052117:Benzodioxoles; D004791:Enzyme Inhibitors; C534333:JZL 184; D010880:Piperidines; D012333:RNA, Messenger; D009538:Nicotine; D008994:Monoacylglycerol Lipases