Endocannabinoid modulation of circadian- and stress-dependent effects on short-term memory in rats

The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges. CB1 receptors are highly expressed within cortico-limbic brain areas, where they modulate stress effects on memory processes. Glucocorticoid and endocannabinoid release is influenced by circadian rhythm. Here we evaluated: i) how different stress intensities, experienced soon after encoding, influence rat short-term memory in an object recognition task, ii) whether the effects depend on circadian rhythms and, iii) if exogenous augmentation of anandamide levels could restore any observed impairment. Two separate cohorts of male adult Sprague-Dawley rats were tested at two different times of the day, morning (inactivity phase) or afternoon (before the onset of the activity phase). The anandamide hydrolysis inhibitor URB597 was intraperitoneally administered immediately after the training trial of the object recognition task. Rats were thereafter subjected to a forced swim stress under low or high stress conditions and tested 1-h after training. Control rats underwent the same experimental procedure except for the forced swim stress (no stress). The low stressor impaired 1-h recognition memory performance when animals were tested in the morning. Exposure to the high stress condition impaired memory performance independently of the time of day. URB597 (0.3 mg kg-1) rescued the altered memory performance in all groups tested both in the morning or afternoon. Our findings demonstrate that stress impairing effects on short-term recognition memory are dependent on the intensity of stress and circadian rhythm. URB597 is capable to specifically counteract these detrimental effects.