Olanzapine And Haloperidol Reverse The Cognitive Deficits Induced By MK-801 Of Adult Rats And Its Mechanism

Objectives To build cognitive impairment animal model mimicking schizophrenia's symptoms,we have chose to use chronic intraperitoneal injection MK-801 method,and evaluated the behavioral alternations induced by MK-801.Then we have attempted to restore MK-801 induced impairments in rats by pre-injected anti-psychotic drugs,and explored the molecular mechanism underlies in the behavioral alternations.Methods Forty-eight Sprague-Dawley rats at the beginning were randomly divided into four groups,veh group?MK-801group?HPD group?Ola group,these four groups were treated normal saline,normal saline +MK-801,and MK-801+pre-haloperidol,MK-801+Olazapine,respectively.After exposed to 22 days' injection,rats have been applied diverse behavioral protocol to assess the alternations in locomotor activity,short-term object-in-context test,long-term object-in-context test,reference memory task,reversal learning task.Then we have utilized Western Blot method to detect the variations of prefrontal cortex and hippocampus' s protein levels in NMDA receptor subunits and their phosphorylated forms,SNARE family proteins and Nectins included.Results 1 The differences between groups of total distance in locomotor activity did not reach significant standard(P?0.05).With regarding to every 5min distance,there is significant time effect(F8,320 = 179.62,P <0.001),however group effect(F3,44 = 2.026,P=0.126)and interact effect(F24,320=1.042,P=0.412)did not have statistical significance;2 The results of short-term object-in-context test have showed that group difference had reached significant standard in preference index(F3,40=3.031,P=0.041),Post-hoc comparison have found that MK-801 rats and HPD rats behave perishing,compared with Veh rats(P<0.05);3 The difference of long-term object-in-context test between groups reached significant level in preference index(F3,40=3.169,P = 0.035),Post-hoc comparison found that MK-801 rats and HPD rats behaved perishing,compared with Veh rats(P<0.05);4 In reference memory task,four groups rats had paralleled level in target quadrant explore time percent(P ? 0.05);5 In reversal learning task,four group's performance of new quadrant exploring time percent varied significantly(F3,42 =5.569,P=0.003),Post-hoc comparison found that MK-801 rats,HPD rats behaved perishing,compared with Veh rats(P<0.05);6 The protein levels of MK-801 rats prefrontal cortex's Glu N1,p Glu N1,Glu N2 A,p Glu N2 B and Glu N2 B were significantly less than Veh rats'(P<0.05),and Ola rats had significantly more expression of Glu N1,p Glu N1 and p Glu N2 B than MK-801 rats(P<0.05),not HPD rats.7 In hippocampus,the expression of MK-801 rats' p Glu N2 A was significantly lower than Veh rats'(P<0.05),and Ola rats' p Glu N2 A was significantly highr than Veh rats'(P<0.05).There were no significant difference in other NMDA receptor subunits(P?0.05);8 In prefrontal cortex,Glu A1 and PSD-95 expressions of MK-801 rat were significantly less than Veh rats'(P<0.05);9 In hippocamp there were no significant difference in Glu A1 and PSD-95(P?0.05);10 In prefrontal cortex and hippocampus,there were no significant difference in Syntaxin1,SNAP25,VAMP1 and EAAT(P?0.05);11 In prefrontal cortex and hippocampus,there were no significant difference in nectins(P?0.05)Conclusions 1 Chronic injections of MK-801 have successfully mimicked cognitive impairment in various behavioral test,such as locomotor activity,short-term object-incontext test,long-term object-in-context test and reversal learning task.And the cognitive impairment could be restored by Olazapine,not haloperidol.2 p Glu N1 and p Glu N2 B in prefrontal cortex and p Glu N2 A in hippocampus were engaged into the molecule mechanism of Olazapine's ameliorative effect for MK-801-induced impairment.