MK-801Induced Rat Models Of Core Symptoms Of Schizophrenia With Different Administration Regimens

Objectives:(1). Aimed to tests the "two-hit" neurodevelopmental hypothesis of schizophrenia in rat model.(2). To disassociates visual memory impairment from other NMDAR antagonist-induced side effects, such as hyperlocomotion, stereotypy, and sensorimotor gating deficits.(3). To explore whether NMDAR antagonist-induced specific phenotypes were corresponding to specific neural pathological mechanisms.Methods:(1). Neonatal NMDAR antagonist MK-801chronic administration (0.1mg/kg.d,0.3mg/kg.d,0.5mg/kg.d, P7-P21) and adolescent social isolation rearing (P21-P49) were combined to construct a "two-hit" model in SD rats. Locomotion, sensorimotor gating, visual memory and anxiety were examined by Open Field test, Prepuls Inhibition of the startle reflex test (PPI), Novel Object Recognition Test (NORT) and Elevated Plus Maze Test respectively.(2). We systematically examined the effects of low to moderate doses (0.01-0.3mg/kg) of MK-801on cognition impairment, locomototion and sensorimotor gating deficits in adult SD rats. The cognition impairment was evaluated by NORT, sensorimotor gating was tested by PPI, and locomotion was measured by open field test. We further examined the effects of different administering time of MK-801and antipsychotics (clozapine,5mg/kg) on visual memory performance in NORT.(3). Akt phosphorylation changes in mPFC and vHIP induced by different acute doses of MK-801(0.001-0.3mg/kg) were evaluated by Western blot. The change of concentrations of DA, DOPAC, HVA,5-HT,5-HIAA, Glu, Gln and GAB A in mPFC and THA induced by different acute doses of MK-801(0.001-0.3mg/kg) were examined with HPLC.Results:(1). Social isolation rearing in adolescence but not neonatal MK-801administration increased the locomotion and decreased the resting time in open field test and increased the anxiety in elevated plus test in puberty; The higher dose of MK-801(0.5mg/kg) neonatal administration but not social isolation rearing impaired visual memory in NORT in puberty; Both neonatal MK-801administration and social isolation rearing have no effects on PPI.(2). At the dose of0.1mg/kg, MK-801significantly inceresed the startle amplitude and decreased the percentage of PPI at all three prepulse levels; At the dose of0.3mg/kg, MK-801was most effective in decreasing the sensorimotor gating levels and was most effective in inducing hyperlocomotion. In contrast,0.03mg/kg of MK-801was most effective in impairing visual memory in NORT while leaving locomotion and sensorimotor gating abilities unaffected.(3). Western blotting showed that0.03mg/kg of MK-801were most effective in decreasing Akt phosphorylation (the ratio of phospho-Akt/total Akt) in mPFC when administered15min and30min before execution. No significant effect of all doses of MK-801on Akt phosphorylation was observed in vHIP. HPLC test showd that0.03mg/kg of MK-801significantly increased the concentration of Glu in the mPFC, while0.1mg/kg of MK-801significantly decreased the concentration of GAB A in THA. At the higher dose of0.3mg/kg, MK-801significantly increased the concentration of DA metabolits HVA in mPFC.Conclusions:(1). Neonatal NMDA receptor blockade and adolescent social isolation rearing did not intercat with each other to bring more severe schizophrenia-like phenotypes in puberty of the "two-hit" neurodevelopmental rat model.(2). MK-801induces different schizophrenia related phenotypes in SD rats with different sensitivities. At a lower dose of0.03mg/kg, MK-801induce selective visual memory impairment which could not be reversed by clozapine; At a moderate dose of0.1mg/kg, MK-801selectively increased startle amplitude and reach the threshold to impair PPI; At a higher dose of0.3mg/kg, MK-801severely impaired PPI and increased locomotion.(3). Different doses of MK-801may have different psychotomimetic effects through targeting different brain regions and different transmitter systems. At a lower dose of0.03mg/kg, MK-801may impair visual memory encoding through decreasing the activity of AKT signal pathway and over-excitation of mPFC. At dose of0.1mg/kg, MK-801may increase the startle amplitude and impair PPI through decreasing the inhibition in THA. At dose of0.3mg/kg, MK-801may increase locomotion through increase DA release in mPFC.