Addition of a 5-HT receptor agonist to methylphenidate potentiates the reduction of [I-123]FP-CIT binding to dopamine transporters in rat frontal cortex and hippocampus

The neurotoxic potential of amphetamine and related drugs is well documente d. However, methylphenidate, an amphetamine derivative used in the treatmen t of attention deficit hyperactivity disorder, and known to increase synapt ic dopamine (DA) levels, seems to lack neurotoxic potential. It is hypothes ized that both dopaminergic and serotonergic systems are involved in the ne urotoxicity of amphetamine derivatives. The purpose of the present study wa s to evaluate the neurotoxic potential of methylphenidate and to test wheth er stimulation of the serotonergic system may confer neurotoxic properties to methylphenidate for DA or serotonin (5-HT) neurons. In addition, the pre sent study was undertaken to evaluate the necessity to perform future SPECT studies in individuals using both methylphenidate and Ei-HT-acting agents. We therefore measured monoaminergic transporters in rat brain using radiol igands suitable for SPECT imaging ([I-123]beta -CIT and [I-123]FP-CIT). Gro ups of rats were treated with methylphenidate or saline for 4 days. Additio nal groups were treated with the selective 5-HT2 receptor agonist quipazine or the selective 5-HT reuptake blocker fluoxetine, alone or in combination with methylphenidate. Binding studies were performed 5 days after the last treatment. In a second experiment, methylphenidate in combination with qui pazine, along with a control group, was retested. In this experiment, monoa minergic terminal density was estimated 2 weeks (rather than 5 days) after drug treatment. Five days, but not 2 weeks, after treatment a significant r eduction in specific [I-123]FP-CIT binding was observed in the frontal cort ex and hippocampus of rats treated with methylphenidate in combination with quipazine. These changes probably do not reflect neurotoxic changes of fro ntal cortex and hippocampal DA terminal markers, but a compensatory downreg ulation of DA transporters. These findings suggest potential harmful effect s of concomitant use of drugs directly activating 5-HT2 receptors in patien ts using methylphenidate. (C) 2001 Wiley-Liss, Inc.