Molecular mechanism for methamphetamine-induced memory impairment

Methamphetamine is a highly addictive drug of abuse, addiction to which has increased to epidemic proportions worldwide. It has been suggested that chronic use of methamphetamine causes long-term cognitive deficits, in addition to psychiatric signs such as hallucination and delusions, which are indistinguishable from paranoid schizophrenia. Neuroimaging studies in methamphetamine abusers have demonstrated that the loss of dopamine transporters in the striatum is related to motor and cognitive impairment. In this review, we will focus on the effect of repeated treatment with methamphetamine on cognitive function in rodents. Repeated methamphetamine treatment in mice impairs long-term recognition memory after withdrawal, which is associated with the dysfunction in dopamine D1 receptor-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the prefrontal cortex. Methamphetamine-induced impairment of recognition memory is reversed by baclofen, clozapine, minocycline and ZSET1446. Repeated methamphetamine treatment in rats also induces impairment of spatial working memory, which is accompanied by the dysfunction of ERK1/2 pathway in the hippocampus. Repeated administration of clozapine, but not haloperidol, improves methamphetamine-induced spatial working memory impairment. These findings suggest that ERK1/2 plays an important role in memory impairments induced by repeated methamphetamine treatment. These animal models of cognitive deficits may be useful to predict the clinical effects of antipsychotics in methamphetamine psychosis and other mental disorders such as schizophrenia.