Striatal dopamine deficiency is the core feature of the pathology of Parkinson's disease (PD) and dopamine replacement with L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay of PD treatment. Unfortunately, chronic L-DOPA administration is marred by the emergence of dyskinesia and wearing-off. Alternatives to L-DOPA for alleviation of parkinsonism are of interest, though to date none can match the efficacy of L-DOPA. Catechol-O-methyltransferase and monoamine oxidase inhibitors are currently used to alleviate wearing-off, but they do not increase on-time without exacerbating dyskinesia. Alternate approaches to dopamine replacement in parkinsonism generally, and to wearing-off and dyskinesia specifically, are therefore urgently needed. Inasmuch as they increase synaptic dopamine levels, dopamine transporter (DAT) inhibitors, be they selective or having actions on noradrenaline or serotonin transporters (NAT and SERT), theoretically represent an attractive way to alleviate parkinsonism per se and potentially enhance L-DOPA anti-parkinsonian action [provided that sufficient dopamine terminals remain within the striatum]. Several non-human primate studies and clinical trials have been performed to evaluate the potential of DAT inhibitors for PD. In this article, following a review of non-human primate studies and clinical trials, we summarise the current knowledge of DAT inhibitors in PD and propose a hypothesis as to how tailoring the selectivity of DAT inhibitors might maximise the benefits of DAT inhibition in PD.
- The American Society for Pharmacology and Experimental Therapeutics