Effects On PKA And CaMKIV By Adenosine And Its Receptors In Rapid Antidepressive Mechanisms Of Sleep Deprivation

Backgrounds and objective:Depression is a kind of psychiatric disease in the world which serious harm human health of body and mind, so that explore a fast effective antidepressant treatment has important value. Sleep deprivation can play fast antidepressant effect, but so far the neurobiological mechanism is not clear. In sleep deprivation it can be found that in the process extracellular adenosine level increased significantly and adenosine receptors also happen a series of corresponding change. Adenosine is an important kind of neuromodulator that can adjust different neurotransmitters release, and it could also participate in sleep adjustment as a sleep factor. Adenosine system plays an important part in sleep deprivation antidepressant mechanism and the pathogenesis of depression. Numerous studies have found that the abnormality of intracellular signaling pathways is an important factor in depression. PKA and CaMKIV are two different key kinases on intracellular signaling pathways. Therefore,we studied the effects of 72 hour rapid-eye-movement sleep deprivation (REMSD) and adenosine A1 and A2A receptor antagonists on the level of PKA and CaMKIV in hippocampus and prefrontal cortex 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 methods:Experimental animals were 56 adult males Sprague-Dawley rats. The weight is about 220-260g.They were divided into two groups randomly: normal control group (n=8) and the stress-model group (n=48). The stress-model group used chronic mild unpredicted stress (CMUS) and Single cage solitary raise way to establish depression model. The stress-model group were divided into six groups in randomized method: the depression-model group(n=8), depression-model + 72 hours sleep deprivation group(n=8), depression-model + 72 hours tank control group(n=8), depression-model+ 72 hours sleep deprivation + adenosine A1 receptor antagonists group(n=8), depression-model + 72 hours sleep deprivation + adenosine A2A receptor antagonists group(n=8), depression-model + 72 hours sleep deprivation + saline group(n=8). The REMSD group used a small platform water environment to sleep deprivation, in order to remove the influence of the water environment. A big platform was used as a control condition. Adenosine A1, A2A receptor antagonist and saline were given into the rats by intraperitoneal injection at 0h, 24h, 48h and 72h respectively in 72h REMSD process. In the experiment we used spontaneous movements test, forced swimming test and sucrose consumption test to observe the changes of depression behavior about rats. We detected the changed level of CaMKIV and PKA about hippocampus and prefrontal cortex with the method of immunohistochemistry. Excel 2003 and SPSS 13.0 statistical software were used for the analysis.Results:1. Sucrose consumption test:After the 21 CMUS the sucrose intake and the sucrose consumption percentage in the CMUS group were lower than those in the control group, the difference between the control and CMUS groups was significant.2. Forced swimming test:After the 21 CMUS the immobility time in the CMUS group was longer than that in the control group, he difference between the control and CMUS groups was significant.3. Spontaneous movements:Spontaneous movements decreased in the CMUS treated depressive animal model compare to the normal control rats. Spontaneous movements increased after 72h REMSD. Spontaneous movements of the rats which were treated with adenosine A1 receptor antagonist and adenosine A2A receptor antagonist have changed significantly.4. The level of PKA and CaMKIV1) After the 21 CMUS the PKA level of hippocampus CA3 area of depression model group rats was lower than that of control group. The PKA level of hippocampus CA3 area of depression model group rats was higher than that of itself after 72h REMSD. The PKA level of Adenosine A1 receptor antagonist group was higher than that of depression model group significantly. The PKA level of Adenosine A2A receptor antagonist group had on change compare to that of depression model group. After the 21 CMUS, the changes of the PKA level of hippocampus CA1 area between all groups had no statistics meanings.2) After the 21 CMUS the CaMKIV level of hippocampus CA3 area of depression model group rats was lower than that of control group. The CaMKIV level of hippocampus CA3 area of depression model group rats was increased after 72h REMSD. The CaMKIV level of Adenosine A1 receptor antagonist group was higher than that of depression model group significantly. The CaMKIV level of Adenosine A2A receptor antagonist group had on change compare to that of depression model group. After the 21 CMUS, the changes of the CaMKIV level of hippocampus CA1 area between all groups had no statistics meanings.3) After the 21 CMUS the PKA level of prefrontal cortex of depression model group rats was lower than that of control group. The PKA level of prefrontal cortex of depression model group rats was higher than that of itself after 72h REMSD. The PKA level of Adenosine A1 and A2A receptor antagonist group was higher than that of depression model group significantly. After the 21 CMUS, the changes of the PKA level of prefrontal cortex between all groups had no statistics meanings.Conclusions:1. CMUS can lead to depressive behavior in rats, and 72 h REMSD can reverse of this change quickly. Combined with using adenosine A1 and A2A receptor antagonist in the 72h REMSD process the depression behavior can be still meliorated.2. The PKA level of prefrontal cortex and hippocampus CA3 area dropped and the CaMKIV level of hippocampus CA3 area dropped either, the 72h REMSD can reverse this effect. So that Chronic stress can lead to the decrease of levels of PKA and CaMKIV and also lead to depression behavior. The reverse effects on behavior about 72h REMSD may contribute to the increased level of PKA and CaMKIV.3. When the adenosine A1 receptors was antagonist, 72h REMSD can lead to the increase of PKA at prefrontal cortex and hippocampus CA3 area and CaMKIV at hippocampus CA3 area, while when the adenosine A2A receptors was antagonist, we cannot observed any changes. It indicates that the adenosine A2A receptors may change the signaling transduction form the level of PKA and CaMKIV to participate in the REMSD antidepressant effects.