| OBJECTIVE:To assess the anti-emetic potential of granisetron in mice induced by phosphodiesterase-4(PDE4) inhibitor rolipram and the effects of gransetron on the anti-depression and spatial memeory enhancement of rolipram.METHODS:(1) The emetic effect potential of rolipram were evaluated based on the duration of anaesthesia in mice induced by the combination of katamine and xylazine, which was determined as the time between the loss and regaining of the (PEG200,60%, V/V), rolipram 0.5 mg·kg-1, rolipram 0.5 mg·kg-1+granisetron (0.05,0.5 and 5 mg·kg-1), granisetron 0.5 mg·kg-1. Sixty min before the induction of anaesthesia, mice were injected intraperitoneally with different doses of granisetorn followed by rolipam subcutaneously forty-five min later. The duration of anaesthesia was assessed by the recovery of righting reflex. (3) Male KM mice were randomly divided into 6 groups:vehicle control (PEG200,60%, V/V), rolipram 0.5 mg·kg-1, rolipram 0.5 mg·kg-1+granisetron (0.05,0.5 and 5 mg·kg-1), escitalopram (ESC,10 mg·kg-1). Ninety min before forced swimming test, mice were injected intraperitoneally with increasing doses of granisetom or escitalopram followed by rolipam subcutaneously forty-five min later. Mice was forced to swim or suspended individually by paper clamp in a glass cylinder filled with water, immobility time was tested as the total duration that the mices showed no movement in the last 4 min during the whole 6 min of the observation. (4) Male KM mice were randomly divided into 6 groups:rolopram (PEG200,60%, V/V), rolipram 0.5 mg·kg-1, rolipram 0.5 mg·kg-1+granisetron (0.05,0.5 and 5 mg·kg-1), granisetron 0.5 mg·kg-1. Ninety minutes before swimming training, mice were injected intraperitoneally with increasing doses of granisetorn followed by rolipram subcutaneously forty-five min later, once a day for consecutive 4 days. The escape latency was test on the fourth day after drug administration, The number of crossings in the target quadrant was test on the fifth day with removing the platform followed by drug administration. The number of the mice crossed the actual location where the platform had been located was measured as the number of crossings in the target quadrant.RESULTS:(1) Rolipram in different dosage significantly reduced duration of anaesthesia induced by ketamine/xylazine in KM mice (F=3.462, P=0.024). The vehicle-treated mice needed an average of 49 min to regain of the righting reflex, rolipram 0.05 mg·kg-1 needed 34.4±19.4 min (P=0.018), rolipram 0.5 mg·kg-1 needed 31.2±12.5 min (P=0.004), While rolipram Smg·kg-1 needed 36.6±14.0 min (P=0.041). (2) Compared with the control group, rolipram 0.5 mg·kg-1 significantly reduced duration of anaesthesia induced by ketamine/xylazine from the control 48 min to 30 min. After combined granisetron at three dosage,the duration of anaesthesia increased to 39.5±15.5 min (P=0.092),43.1±17.7 min (P=0.022),42.1±16.6 min (P =0.033). There was no difference between rolipram 0.5 mg·kg-1 and the combined group (F=1.930, P=0.139). (3) The average of immobility time of the control group in forced swinming test was 182 s, rolipram reduced to 133 s. Which indicated that rolipram can raise activity of mice in despair. immobility time of the 3 combination group respectively was 135±66s,93±36 s,132±64 s. No significant difference was observed among rolipram group and 3 combination groups (F=1.112, P=0.361). In tail suspension test, the average of immobility time of the control group was 167 s, while the rolipram group was 116 s (P=0.035), which was not significantly different with the 3 combination group (135±66 s,93±36 s and 132±64 s). (4) Compared with control group, ralipram group and 3 combination group all reduced the escape latency on the fourth day (P<0.05). while, among the 4 group there was no significant different (F=0.038,P=0.990).The average number of crossings in the target quadrant of control group was 1.7, while the rolipram group significantly increased to 3.9±2.5 s After combination of 3 dosage of granisetron, The average number of crossings in the target quadrant was 3.3±2.3,3.8±2.2,3.5±2.1 s. It did not show significant different among rolipram and the combination group. Similar phenomenon was showed in percent time in the target quadrant, granisetron did not influence the percent time (F=0.503, P=0.682). in short, rolipram combined with granisetron did not influence the antidepressant effect and spatial memory performance improvement of rolipram.CONCLUSION:Rolipram combined with granisetron can significantly reduce the vomiting and emetic potential of rolipram, without intervention on its antidepressant effects or cognitive enhancement. So the combination of rolipram combined and granisetron is a potential effective treatment to avoid nausea and vomiting in pharmacological therapy. |
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