Synergistic action of arachidonylcyclopropylamide and yohimbine in alleviating acute stress-related emotional memory deficits in mice

Stress may exhibit contradictory effects on learning and memory processes. The endocannabinoid and noradrenergic systems have been implicated separately in modulating stress responses and memory formation; however, their interactions in avoidance memory processing under stress have received little attention so far. The step-down test was used to evaluate the memory abilities of male Naval Medical Research Institute (NMRI) mice. Acute restraint stress (ARS) for 4 h reduced step-down latency in mice, indicating stress-induced amnesia. The intracerebroventricular microinjection of the cannabinoid CB1 receptor (CB1R) agonist arachidonylcyclopropylamide (ACPA; 0.25 and 0.5 µg/mouse) prevented the amnesia induced by ARS. The microinjection of a lower dose of ACPA in conjunction with the α₂-noradrenoceptor agonist clonidine (0.25 and 0.5 µg/mouse) resulted in an enhancement of memory retention in non-ARS (NARS) and ARS mice. Meanwhile, ARS impaired memory retention in mice administered with clonidine (0.25 µg/mouse). Moreover, mice received different doses of the α₂-noradrenoceptor antagonist yohimbine (0.25 and 0.5 µg/mouse) in the presence or absence of ACPA demonstrated successful memory retention. Synergistic effect of ACPA and yohimbine was presented by the isobologram analysis. However, none of the treatments had any effect on mice's locomotion. These results suggest that targeting both CB1 and α₂-noradrenergic receptors may offer a potential therapeutic strategy for mitigating stress-induced memory deficits.