Augmentation of L-DOPA-evoked dopamine efflux by Methylphenidate : role for the D2 autoreceptor?

Using a 6-OHDA model of Parkinson’s disease, we have preliminary evidence that L-DOPA-derived dopamine (DA) ceases to be released through conventional mechanisms of exocytosis under severe denervation. This may be problematic, as large, and possibly unregulated release of L-DOPA-derived DA would be expected to cause abnormal patterns of DA stimulation at the postsynaptic receptors, likely contributing to the development of dyskinesia. This issue may be overcome with the Dopamine Transporter (DAT) blocker Methylphenidate (MPD). Ahn and Phillips observed that MPD augmented the L-DOPA-derived DA efflux in a manner consistent with the under-appreciated fact that MPD also acts as a vesicular monoamine transporter (VMAT2) agonist (Volz, 2008), thereby facilitating the sequestration of cytosolic DA into vesicles, where it could enter into a cycle of impulse-dependent release processes. The hypothesis that MPD may influence the sequestration and release of L-DOPA-derived DA into presynaptically-regulated mechanisms of exocytosis may have beneficial therapeutic implications. Thus, the two major objectives of this thesis were first to assess whether L-DOPA-derived DA remained under presynaptic D2 autoreceptor regulation dependent on the severity of striatal denervation, and second, to investigate the mechanism(s) by which MPD may facilitate vesicular DA release, possibly by involvement of the D2 autoreceptor. L-DOPA was reverse-dialyzed into the intact and 6-OHDA lesioned dorsal striatum of the rat, followed by the reverse-dialysis of the D2 autoreceptor agonist and antagonist, Quinpirole and Eticlopride, or the VMAT2 inhibitor, Tetrabenazine. Although L-DOPA-evoked DA efflux remained under D2 autoreceptor control in the intact and moderately lesioned striatum, in the case of severe, 95% denervation, L-DOPA-evoked DA efflux was unaffected by D2 autoreceptor regulation or VMAT2 inhibition. However, despite the apparent loss of autoreceptor regulation, a subsequent study found that inhibitory binding of the D2 autoreceptor by reverse-dialysis of Eticlopride into the severely denervated striatum prior to the administration of MPD, completely blocked MPD-induced augmentation of L-DOPA-derived DA. These results implicate the D2 autoreceptor in a novel mechanism by which MPD can facilitate DA neurotransmission, and suggest that even under conditions of severe denervation, the presynaptic D2 autoreceptor may be manipulated pharmacologically to facilitate the exocytotic release of L-DOPA-derived DA.

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