Dual Fatty Acid AmideHydrolase and MonoacylglycerolLipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

摘要

Acute administration of Δ⁹-tetrahydrocannabinol (THC) or exposure to marijuana smoke impairs short-term spatial memory in water maze tasks through a CB1 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 CB1 receptor antagonist rimonabant. Neither JZL184 nor JZL195impaired performance in a cued version of the water maze task, arguingagainst the notion that sensorimotor or motivational deficits accountedfor the impaired acquisition performance. JZL184 increased 2-AG levelsin the hippocampus, prefrontal cortex, and cerebellum to a similardegree in FAAH −/– and +/+ mice. FAAH −/–mice, regardless of drug treatment, possessed elevated AEA levelsin each brain region assessed. The results of this study reveal thatconcomitant increases in AEA and 2-AG disrupt short-term spatial memoryperformance in a manner similar to that of THC.