Molecular mechanisms of the methylphenidate-induced psychostimulus effects

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Methamphetamine is a powerfully addictive psychostimulant that dramatically affects the mammalian central nervous system. Methylphenidate, which has been known to have psychostimulus effects similar to methamphetamine, is commonly used in the treatment of narcolepsy and serious depression and with children and adolescents who have attention deficit/hyperactivity disorder. In the present study, I investigated the abuse potentiality of methylphenidate, compared to that of methamphetamine. The subcutaneous administration of either methamphetamine or methylphenidate increased the extracellular dopamine levels in the nucleus accumbens of mice. The stimulation of dopamine release by methamphetamine or methylphenidate was suppressed by pretreatment with an intra-nucleus accumbens injection of a selective phosphoinositide 3-kinase (PI3-K) inhibitor wortmannin. Interestingly, methamphetamine, but not methylphenidate, also increased the extracellular 5-HT levels in this area. Furthermore, repeated treatment with methamphetamine aggravated the development of sensitization to hyperlocomotion, whereas methylphenidate failed to induce behavioral sensitization. Moreover, in vitro treatment with methamphetamine caused a long-lasting astrocytic activation in limbic neuron/glia cocultures, but methylphenidate failed to cause such an effect.These findings suggest that unlike methamphetamine, methylphenidate shows a lack of the development of behavioral sensitization to its hyperlocomotion and induces the reversible astrocytic activation. Furthermore, the enhancement of 5-HT release by methamphetamine may, at least in part, contribute to the development of behavioral sensitization and irreversible changes in astrocytic function after methamphetamine treatment.