Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity

Abstract

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic-pituitary-adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory.

Figure 1

Behavioral effects during object recognition training in rats in the WITHOUT-habituation and WITH-habituation conditions. Rats in the WITHOUT-habituation (WITHOUT) condition spent significantly less time exploring the two identical objects during the training trial as compared with rats in the WITH-habituation (WITH) condition (a). Conversely, rats in the WITHOUT-habituation condition showed a higher number of crossings (b) and rearings (c) during training as compared with rats in the WITH-habituation condition. **P<0.01 vs the WITH-habituation group. Data are expressed as mean±SEM (n=48 per group).

Figure 2

Effect of posttraining administration of WIN55,212-2 on 1-h retention of rats in the WITHOUT- and WITH-habituation conditions. Posttraining administration of WIN55,212-2 (WIN, 0.3 mg/kg, i.p.) impaired 1-h retention of object recognition memory of rats in the WITHOUT-habituation condition (a) but enhanced 1-h retention of rats in the WITH-habituation condition (b). *P<0.05 vs the corresponding vehicle control group. Data are expressed as mean±SEM (n=12 per group).

Figure 3

Effect of posttraining administration of WIN55,212-2 on 24-h retention of rats in the WITHOUT- and WITH-habituation conditions. Posttraining administration of WIN55,212-2 (WIN, 0.3 mg/kg, i.p.) enhanced 24-h retention of object recognition memory of rats in the WITHOUT-habituation condition (a) and did not significantly affect 24-h retention of rats in the WITH-habituation condition (b). *P<0.05 vs the corresponding vehicle control group. Data are expressed as mean±SEM (n=10–14 per group).

Figure 4

Effect of object recognition training and posttraining administration of WIN55,212-2 on plasma corticosterone levels in rats in the WITHOUT- and WITH-habituation conditions. Plasma corticosterone levels in rats in the WITHOUT-habituation condition treated with vehicle posttraining were significantly higher than those in vehicle-injected rats in the WITH-habituation condition, as assessed 30 min after training; *P<0.05 vs vehicle-treated rats in the WITH-habituation condition. Further, plasma corticosterone levels in vehicle-treated trained rats in both the WITHOUT- and WITH-habituation conditions were significantly higher than those in non-trained vehicle-treated rats; ^♦♦P<0.01 vs vehicle-treated not exposed rats. WIN55-212,2 (WIN, 1 mg/kg, i.p.) administered immediately after object recognition training increased plasma corticosterone levels in rats in the WITHOUT-habituation condition; ^##P<0.01 vs the corresponding vehicle-treated control group. In contrast, WIN55,212-2 (0.3 mg/kg, i.p.) decreased plasma corticosterone levels in habituated rats; ^#P<0.05 vs the corresponding vehicle-treated control group. Data are expressed as mean±SEM (n=4–7 per group).

Figure 5

Effect of pretreatment with metyrapone on the effect of posttraining administration of WIN55,212-2 on 1- and 24-h retention of rats in the WITHOUT-habituation condition. Metyrapone (Mety, 35 mg/kg, i.p.) administered to rats in the WITHOUT-habituation condition 40 min before object recognition training reverted the impairing effect of posttraining WIN55,212-2 (WIN, 0.3 mg/kg, i.p.) on 1-h retention (a) and the enhancing effect of WIN55,212-2 (0.3 mg/kg, i.p.) on 24-h retention (b). Both 1- and 24-h retention performance became very similar to those observed in low-aroused rats in the WITH-habituation condition (see Figures 2b and 3b). *P<0.05; **P<0.01 vs the corresponding vehicle group, ^##P<0.01 vs the WIN55,212-2 alone group. Data are expressed as mean±SEM (n=9–12 per group).