Differences in neuronal toxicity and its molecular mechanisms between methamphetamine and methylphenidate

: Methylphenidate (MPH) is commonly used in the treatment of narcolepsy and attention deficit/hyperactivity disorder (AD/HD) in Japan. MPH has been also known to have psychostimulus effects similar to methamphetamine (METH). In the present study, we compared several effects of MPH to METH. It is well-known that the repeated administration of psychostimulant drugs induces behavioral sensitization. However, MPH failed to induce sensitization to hyperlocomotion, while METH clearly induced behavioral sensitization. Moreover, the METH-induced rewarding effect was maintained even 2 weeks after withdrawal of METH. In contrast, the MPH-induced rewarding effect almost disappeared within 2 weeks after withdrawal of MPH. We next investigated the effect of METH and MPH on astrocytes, which have been known to play an important role in neuronal network systems. Both METH and MPH induced astrocytic activation in limbic neuron/glia cocultures. It is of interest to note that the METH-induced astrocytic activation was still present after an additional 2 days of culture with normal medium. Unlike METH, the MPH-induced astrocytic activation was reversed within 2 days after washout of MPH. Furthermore, high concentration of METH, but not MPH, reduced MAP2a/b positive cells and activated the immunoreactivity of the cleaved caspase-3 in primary cultured limbic neurons, whereas MPH had no such effect. Taken together, the present findings suggest that the psychostimulus effects of METH and MPH occur through different mechanisms.