Effect Of (m)VD-Hpα, A Cannabinod Receptor Type1 Agonist, On Sleep-Wake States In Rats

The endogenous cannabinoid system(ECS) in the central nervous system regulates emotion, appetite, cognition, autonomic behavior and autonomic nerve function. Several exogenous or endogenous cannabinoids, most of those as sleep promoters except cannabidiol(CBD), have been proved to regulate sleep-wake behavior,(m)VD-Hpα [VDPVNFKLLSH-OH,(m)VD-hemopressin(α)] is a cannabinoid reptor type 1(CB1) agonist extracted recently from mouse brain tissue and has been demonstrated to generate several functions, such as analgesic,hypotensive, hypothermia, and reduce activity, however whether involved in regulation of sleep-wake behavior remains unknown. The present study was designed to detect the effect and potential mechanism of(m)VD-Hpα on the sleep-wake behavior.Methods:Intracerebroventricular injection(ICV) of 13.4, 20.1, 40.2 nmol endogenous peptide CB1 receptor agonist(m)VD-Hpα in rats at the beginning of light off period(20:00). ICV injection of 7.5 nmol synthetic non-peptide CB1 receptor agonist WIN55,212-2 at the same time as positive control. The electroencephalogram(EEG)recorded for 24 h after drug administration was served as a tool to observe and analyze the change of the rat sleep-wake behavior. c-Fos immunohistochemistry was used to mark the active neurons in several sleep-wake related brain regions.Results:1. Compared with saline group, 13.4, 20.1, 40.2 nmol(m)VD-Hpα shorten the latency of PS, there isn’t significant effect on the latency of SWS.(m)VD-Hpα increase the time spent on PS in the first 4 h post-injection, the median dose(20.1 nmol) increase the PS episode occurrences without change the PS episode duration, and its PS promoting effect could be accumulated in the whole recording period.2. Compared with saline group, 20.1 nmol(m)VD-Hpα significantly increase the total time of PS in the dark/active phase but not change the total time of PS in the light on period. The total time of PS in the whole recording period(24 h) were changed by 20.1 nmol(m)VD-Hpα as well. Compared with vehicle group,WIN55,212-2 increase the time spent on PS after 12 h post-injection(the light/inactive phase).3.(m)VD-Hpα induced an increase of Fos-ir neurons in VLPO and PPT, reduced the Fos-ir neurons in LH. WIN55,212-2 increased the Fos-ir neurons in VLPO and LDT.Conclusion:(m)VD-Hpα shorten the latency of PS. Both(m)VD-Hpα and WIN55,212-2 can increase the time of PS admitting that the working time of WIN55,212-2 appeared later. 20.1 nmol(m)VD-Hpα changed the sleep-wake cycle of rats, increase the occurrences of PS without change the PS duration. The neurons in LH, VLPO, PPT and LDT may be involved in the regulation of sleep-wake behavior of(m)VD-Hpα.