title: Dual fatty acid amide hydrolase and monoacylglycerol lipase blockade produces THC-like Morris water maze deficits in mice.
abstract: Acute administration of Δ(9)-tetrahydrocannabinol (THC) or exposure to marijuana smoke impairs short-term spatial memory in water maze tasks through a CB(1) receptor mechanism of action. N-Arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids that are predominantly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Although the MAGL inhibitor JZL184 enhances short-term synaptic plasticity, it has yet to be evaluated in the Morris water maze. Previous research demonstrated that simultaneous, complete blockade of FAAH and MAGL produces full blown THC-like effects. Thus, in the following studies we tested whether dual blockade of FAAH and MAGL would impair learning in a repeated acquisition Morris water maze task. Mice treated with the dual FAAH/MAGL inhibitor JZL195 (20 mg/kg) as well as JZL184-treated FAAH -/- mice displayed robust deficits in Morris water maze performance that were similar in magnitude to THC-treated mice. While 20 or 40 mg/kg impaired water maze performance in FAAH -/- mice, only the high dose of JZL184 disrupted performance in FAAH +/+ mice. The memory impairing effects of JZL184 were blocked by the CB(1) receptor antagonist rimonabant. Neither JZL184 nor JZL195 impaired performance in a cued version of the water maze task, arguing against the notion that sensorimotor or motivational deficits accounted for the impaired acquisition performance. JZL184 increased 2-AG levels in the hippocampus, prefrontal cortex, and cerebellum to a similar degree in FAAH -/- and +/+ mice. FAAH -/- mice, regardless of drug treatment, possessed elevated AEA levels in each brain region assessed. The results of this study reveal that concomitant increases in AEA and 2-AG disrupt short-term spatial memory performance in a manner similar to that of THC.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1217 East Marshall Street, P.O. Box 980613, Richmond, Virginia 23298, United States. lewise@vcu.edu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wise
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Long
authors.forename: Rehab A
authors.initials: RA
authors.lastname: Abdullah
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D013759:Dronabinol / Q000633:toxicity*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced* / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D013759:Dronabinol; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases