A novel azaindolizinone derivative ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2.
The effect of ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-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 showed a significant ameliorating effect on METH-induced impairment of recognition memory, although it had no effect on exploratory behavior. ZSET1446 (1 microg/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/extracellular signal-regulated kinase kinase inhibitor, SL327 (alpha-[amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylacetonitrile). 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-aspartate (NMDA) receptor antagonist, MK-801 [5H-dibenzo[a,d]cyclohepten-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.
Ito
Yukio
Y
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan.
Takuma
Kazuhiro
K
Mizoguchi
Hiroyuki
H
Nagai
Taku
T
Yamada
Kiyofumi
K
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation; D007189:Indans / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000201:enzymology; D013141:Spiro Compounds / Q000494:pharmacology*
D001552:Benzazepines; D007189:Indans; D013141:Spiro Compounds; C511224:spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3