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.