Elsevier

Biological Psychiatry

Volume 70, Issue 5, 1 September 2011, Pages 479-486
Biological Psychiatry

Archival Report
Differential Role of Anandamide and 2-Arachidonoylglycerol in Memory and Anxiety-like Responses

https://doi.org/10.1016/j.biopsych.2011.04.022Get rights and content

Background

Cannabinoid agonists are potential therapeutic agents because of their antinociceptive and anxiolytic-like effects, although an important caveat to their use is the possible adverse responses related to memory impairment. An alternative approach to circumvent this limitation consists of enhancing the concentration of the endocannabinoids anandamide and 2-arachidonoylglycerol.

Methods

Using low doses of the specific inhibitors of the endocannabinoid metabolizing enzymes fatty acid amide hydrolase, URB597, and monoacylglycerol lipase, JZL184, we analyzed their acute and chronic effects on memory consolidation, anxiolytic-like effects, and nociception in mice (n = 6–12 per experimental group).

Results

We show that anandamide is a central component in the modulation of memory consolidation, whereas 2-arachidonoylglycerol is not involved in this process. Interestingly, both URB597 and JZL184 induce anxiolytic-like effects through different cannabinoid receptors. In addition, the results show that the antinociceptive and anxiolytic-like responses of both inhibitors, as well as their acute effects on memory consolidation, are maintained after chronic treatment.

Conclusions

These results dissociate the role of anandamide and 2-arachidonoylglycerol in memory consolidation and anxiety and reveal the interest of cannabinoid receptor 2 as a novel target for the treatment of anxiety-related disorders.

Section snippets

Animals

Male Swiss albino and C57BL/6J mice (Charles River, Lyon, France) and CB1 (16) and CB2 (Jackson Laboratory, Bar Harbor, Massachusetts) constitutive knockout mice (8–10 weeks of age), weighing 26 g to 30 g at the beginning of the experiments were used. Mice were housed five per cage in a temperature (21 ± 1°C) and humidity (55 ± 10%) controlled environment. Food and water were available ad libitum. All the experiments were performed during the light phase of a 12-hour light/dark cycle (lights on

Differential Effects of URB597 and JZL184 in Hippocampal Memory and Hippocampal Mammalian Target of Rapamycin Regulation

We used the object-recognition and context-recognition tasks to evaluate the effects of URB597 and JZL184 on memory consolidation. Using these paradigms, robust hippocampal-dependent learning can be achieved in a single training session (19, 21); therefore, memory consolidation can be modified pharmacologically afterward, precluding the possible influence of the acute pharmacologic effects of the drugs on locomotion or exploration during the memory acquisition or retrieval periods. Systemic

Discussion

The modulation of the endocannabinoid system is an emerging therapeutic approach, based on the well-demonstrated medicinal properties of compounds acting on this system (25). Selective and efficacious inhibitors of the two main enzymes involved in the catabolism of AEA and 2-AG, FAAH and MAGL, respectively, have been developed, allowing the selective increase of endocannabinoid concentrations in vivo (6, 7). We took advantage of these pharmacologic tools to modulate the endogenous levels of AEA

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    Authors AB-G and EP contributed equally to this work.

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