A Novel Azaindolizinone Derivative ZSET1446(Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one)Improves Methamphetamine-lnduced Impairment of Recognition Memory in Mice by Activating Extracellular Signal-Regulated Kinase 1/2

摘要

The effect of ZSET1446(spiro[imidazo[1,2-a]pyridine-3,2-in-dan]-2(3H)-one)on cognitive impairment in mice,previously treated with methamphetamine(METH)at a dose of 1 mg/kg for 7 days,was investigated.ZSET1446 snowed a significant ameliorating effect on METH-induced impairment of recognition memory,although it had no effect on exploratory behavior.ZSET1446(1 mu g/kg)recovered the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2(ERK1/2)in the prefrontal cortex(PFC)of METH-treated mice.The compound increased phosphorylated ERK1/2 levels in the hippocampus but not PFC of naive mice without affecting the total ERK1/2 levels.The ameliorating effect of ZSET1446 on recognition memory in METH-treated mice was negated by pretreatment with a mitogen-activated protein kinase/extracel-lular signal-regulated kinase kinase inhibitor,SL327(alpha-[amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylaceto-nitrile).Furthermore,the dopamine D1 receptor antagonist,SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine],and N-methyl-D-aspar-tate(NMDA)receptor antagonist,MK-801 [5H-dibenzo[a,d]cy-clohepten-5,10-imine(dizocilpine maleate)],blocked the ameliorating effect of ZSET1446 on METH-induced memory impairment,whereas the D2 receptor antagonist,raclopride,had no effect.These results suggest that the ameliorative effect of ZSET1446 on METH-induced memory impairment is associated with indirect activation of ERK1/2 following stimulation with dopamine D1 and NMDA receptors of the PFC.ZSET1446 would be a potential candidate for further preclinical study aimed at the treatment of cognitive deficits in Alzheimer's disease and schizophrenia,as well as METH psychosis.