Effects Of Rem Sleep Deprivation On Adenosine A₁ And A_2a Receptor In The Different Brain Regions In Chronic Stresses Treated Rats

Background and ObjectiveUntil recently, the causation of depressive disorders was most explained in terms of abnormalities involving regional modifications of brain structure, neurochemical with bioactivity, receptor regulation and molecular biology. Antidepressant therapy is the process that recovery the homeostatic equilibrium of central nervous system which constitutes a defense mechanism against the deleterious effects of stress. The antidepressant benefit of sleep deprivation is efficacious and rapid, but transient, for it disappear after sleep recovery. It has been known that multi-neurochemical and nervous pathways take parts in its mechanism involving monoamine neurotransmission,adenosine system and different brain regions especially limbic system and midbrain central gray .They each with unique roles interact at the same time. Remarkly, adenosine system has been evidenced that it not only accommodates behavior states including sleep-wake cycle or movement, but also operates neuromodulate effects via the most abundant inhibitory adenosine A1 receptor(A1R) and the less abundant, but widespread, facilitatory A2A receptor(A2AR). In addition, the adenosine system is identified that tightly linked to the pathogenesy and treatment of the depressive disorder. According to the correlation, we studied the effects of 72 hour rapid-eye-movement sleep deprivation (REMSD) and rebound sleep on the expression of A1Rs and A2ARs in dorsal raphe nucleus(DRN), hippocamp(DG) and amygdale(CeA) of chronic mild unpredictable stress (CMUS) animal model to investigate the mechanisms of this antidepressant effects of sleep deprivation and the possible involvement of adenosine receptor.Materials and methodsSprague Dawley rats were divided into two groups randomly: 1) normal control group, 2)the depression-model group, 3)depression-model +sleep deprivation group, 4)depression-model +72 hours tank control group, 5) depression-model +sleep deprivation sleep +rebounded group. Two classical models were adopted to build depression-model, one is chronic mild unpredicted stresses, and the other is sub-raising. The REMSD group used a small platform water environment, in order to remove the influence of the water environment, a big platform was used as a control condition. Spontaneous movements were performed in the 0, 21, 24, 25day of the experiment. Rats were sacrificed, the level of A1Rs and A2ARs mRNA expression were studied by in situ hybridization and DAB staining (brown chromogens). Photomicrographs were taken by high power microscope, and the brown cells were counted by IPP 6.0 image analysis software. Excel 2003 and SPSS 13.0 statistical software were used for the analysis.Results1. Spontaneous movements;1) Spontaneous movements decreased in the CMUS treated depressive animal model compare to the normal control rats. Following 72 h REMSD, spontaneous movements increased, and reduced again after sleep rebounded.2. Adenosine A1 receptor mRNA (A1RmRNA);1) A1RmRNA increased in the DRN after CMUS treatment, and decreased after REMSD compare to the CMUS group, but didn't reach statistics meaning. The rebounded sleep increased the expression of A1RmRNA in REMSD treated rats.2) A1RmRNA increased in the DG of hippocampus significantly after CMUS treatment, and decreased after REMSD compare to the CMUS group. But the sleep recovery had insufficient effect to the REMSD treated rats;3) A1RmRNA did not obviously changed in centronucleus-amygdala (CeA) after CMUS treatment, but increased significantly after REMSD compare to the CMUS group. The rebounded sleep decreased the expression of A1RmRNA in REMSD treated rats.2. Adenosine A2A receptor mRNA (A2ARmRNA);1) A2ARmRNA decreased notably in the DRN after CMUS treatment; and increased after REMSD compare to the CMUS group. The rebounded sleep decreased the expression of A1RmRNA in REMSD treated rats.2) A2ARmRNA did not change very much in the DG of hippocampus after CMUS treatment, and upgraded significantly after REMSD treatments compared to the CMUS group. The sleep recovery decreased the expression of A2ARmRNA in REMSD treated rats, but did not reach the statistics meaning.3) A2ARmRNA increased in CeA markedly after CMUS treatment, but REMSD did not change the level of A2ARmRNA obviously. The sleep recovery significantly increased the expression of A2ARmRNA in REMSD treated rats.Conclusions1)REMSD can be an appropriate and experimental model of antidepressant treatment that offer new pathway to invest the basic neural mechanisms.2)The A1RmRNA increased in the DRN and DG and decreased in the CeA after CMUS treatment; the A2ARmRNA increased in the CeA, decreased in the DRN, but not changed very much in the DG after CMUS treatment. The CMUS had different effects in the three brain regions reseached, A1RmRNA and A2ARmRNA may each had roles in the process of the CMUS to inducing the depression.3)The A1RmRNA decreased in the DRN and DG and increased in the CeA after REMSD treatment; the A2ARmRNA decreased in the CeA and increased in the DRN and DG after REMSD treatment. Most groups of REMSD treatments showing the alteration of adenosine receptor mRNA had the anti-depression effect by itself compare to the water environment group.4) The rebounded sleep returned the A1RmRNA and A2ARmRNA expression in all the brain regions researched pre compare to the REMSD treated group, indicating the involvement of both A1 and A2A receptor's regulation for sleep-wake cycle, and further evidenced the probability of t the two adenosine receptor's participation in the effects of REMSD in antidepressant process.On the whole, adenosine A1 and A2A receptor may fairly have roles in the action of the REMSD for anti-depression; but A1 and A2A receptor may do the different function in the course.