Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation

Abstract

The endocannabinoid system is a key modulator of memory consolidation for aversive experiences. We recently found that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases anandamide levels by inhibiting its hydrolysis, facilitates memory consolidation through a concurrent activation of both cannabinoid receptor type 1 (CB1) and 2 (CB2). Here, we investigated the role played on memory consolidation by the other major endocannabinoid, 2-arachidonoylglycerol (2-AG). To this aim, we tested the effects of pharmacological inhibition of monoacylglycerol lipase (MAGL) through systemic administration of the MAGL inhibitor JZL184 to rats immediately after training of the inhibitory avoidance task. Pharmacological enhancement of 2-AG tone facilitated memory consolidation through activation of CB2 receptor signaling. Moreover, we found that increased 2-AG signaling prevented the activation of the mammalian target of rapamycin (mTOR) signaling pathway in the hippocampus through a CB2-dependent mechanism. Our results identify a fundamental role for 2-AG and CB2 receptors in the modulation of memory consolidation for aversive experiences.

Keywords: Behavior; CB1 receptor antagonist; CB2 receptor antagonist; Fear memory; Inhibitory avoidance; JZL184; JZL184 [4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester]; MAGL inhibitor; Monoacylglycerol lipase (MAGL); Rat; SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-Piperidinyl-1H-pyrazole-3-carboxamide]; SR144528 [5-(4-chloro-3-methylphenyl)-1- [(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo [2.2.1] hept-2-yl] -1H-pyrazole-3-carboxamide].