Endocannabinoid modulation of short-term recognition memory in rats: Influence of stress and circadian rhythm

Background: The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges. We previously demonstrated that different stress intensities, experienced soon after encoding, influenced rat short-term memory in an object-recognition task, and that systemic injection of the anandamide hydrolysis inhibitor URB597 reverted the impairing effects, in a stress- and circadian-dependent manner. The effects of stress on the endocannabinoid system are regionally specific and dependent on time. Methods: Here, we examined whether two different stress intensities and circadian fluctuations on endocannabinoid components modulate short-term memory in the hippocampus, a brain region crucially involved in the modulation of memory. Hippocampal anandamide and 2-arachidonoylglycerol (2-AG) content and the activity of their degrading enzymes, FAAH and MAGL (respectively), were measured. Results: Independently of the time of the day, stress exposure induced an overall decrease of hippocampal anandamide levels. No significant changes were observed in FAAH activity. Exposure to the high stress condition decreased hippocampal 2-AG and, accordingly, increased MAGL activity, selectively when animals were tested in the afternoon. To further investigate hippocampal 2-AG modulation of short-term recognition memory, rats were given bilateral intra-CA1 administration of the 2-AG inhibitor KML29 immediately after the training trial and were thereafter subjected to a forced swim stress under low or high stress conditions. Low stress exposure impaired 1-hr recognition memory performance when animals were tested in the morning. Exposure to high stress impaired memory performance independently of the time of testing. Discussion: KML29 counteracted the detrimental effects of stress on short-term recognition memory.