The Role Of Endocannabinoid Peptide Hemopressin And Derivatives,and Endomorphin-1 In Learning And Memory Of Mice

The cannabinoid system plays an important role in learning and memory processes,many studies have indicated that cannabinoid receptor ligands have ability to modulate memory in rodents.A nonapeptide hemopressin?Hp?derived from rat brain,acts as an antagonist or selective inverse agonist of cannabinoid 1?CB1?receptor.N-terminally extended forms of Hp isolated from mouse brain,?m?RVD-hemopressin????RVD?and?m?VD-hemopressin????VD?also bind CB1receptor,however,as agonists.Here,we investigated the roles of Hp,RVD,and VD on memory in mice using novel object recognition?NOR?and object location recognition?OLR?tasks.In normal young mice,intracerebroventricular infusion Hp not only improved memory formation,but also prolonged memory retention in the tasks.RVD and VD at the same dose inhibited the effects of Hp.Under the same experimental conditions,RVD and VD displayed memory-impairing effects that could be prevented by Hp.Infusion of amyloid-??1-42?(A?_1-42)resulted in impairment of memory in mice which could be used as Alzheimer's disease model mice.In these mice,RVD and VD reversed the memory impairment induced by A?_1-42,and the effects of RVD and VD could be suppressed by Hp.However,separate administration of Hp had no effect in A?_1-42-treated mice.Our results support the hypothesis that the cannabinoid system may be a potential target for therapy in disorders involving abnormal memory.Moreover,Hp,RVD,and VD may be used as drug combinations to treat cognitive disease,especially AD.A growing body of evidence suggests that the agglomeration of A?may be a trigger for AD.Inhibiting the aggregation of A?has been considered a therapeutic strategy for AD.Endomorphin-1?EM-1?,an endogenous agonist of?-opioid receptors,has been shown to inhibit the aggregation of A?in vitro.In the present study,we investigated whether EM-1 could alleviate the memory-impairing effects of A?_1-42 in mice using NOR and OLR tasks.We showed that co-administration of EM-1 was able to ameliorate A?_1-42-induced amnesia in the lateral ventricle and the hippocampus,and these effects could not be inhibited by naloxone,an antagonist of?-opioid receptors.Infusion of EM-1 or naloxone separately into the lateral ventricle had no influence on memory in the tasks.These results suggested that EM-1 might be effective as a drug for AD treatment by inhibiting A?aggregation directly as a molecular modifier.