Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate [Neurobiology]

November 26th, 2013 by Federici, M., Latagliata, E. C., Ledonne, A., Rizzo, F. R., Feligioni, M., Sulzer, D., Dunn, M., Sames, D., Gu, H., Nistico', R., Puglisi-Allegra, S., Mercuri, N. B.

We combined in vitro amperometric, optical analysis of fluorescent false neurotransmitters, and microdialysis techniques to unveil that cocaine and methylphenidate induced a marked depression of the synaptic release of DA in mouse striatum. In contrast to the classical DAT-dependent enhancement of dopaminergic signal observed at concentrations of cocaine lower than 3 uM, the inhibitory effect of cocaine was found at concentrations higher than 3 uM. The paradoxical inhibitory effect of cocaine and methylphenidate was associated with a decrease in synapsin phosphorylation. Interestingly, a cocaine-induced depression of DA release was only present in cocaine-insensitive animals (DAT-CI). Similar effects of cocaine were produced by methylphenidate in both wild-type and DAT-CI mice. On the other hand, nomifensine only enhanced the DAergic signal either in wild or in DAT-CI mice. Overall, these results indicate that cocaine and methylphenidate can increase or decrease DA neuro-transmission by blocking reuptake and reducing the exocytotic release, respectively. The biphasic reshaping of DA neurotransmission could contribute to different behavioral effects of psychostimulants, including the calming ones in attention-deficit hyperactivity disorder.