Received for publication September 19, 2006.
Revised November 2, 2006.
Accepted for publication November 6, 2006.

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

Abstract

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 µg/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 (MEK) inhibitor, SL327. Furthermore, the dopamine D1 receptor antagonist, SCH23390, and NMDA receptor antagonist, MK-801, 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.

Key words: ZSET1446, extracellular signal-regulated kinase 1/2, methamphetamine, prefrontal cortex, recognition memory, schizophrenia

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