Thus, while monoamine re-uptake inhibitors may have potential as therapeutic agents in PD, the drug candidates identified so far may not possess ideal combinations of DAT activity relative to SERT or NET to enhance the actions of LDOPA. We have recently described the discovery of a novel monoamine re-uptake inhibitor, UWA-101 -1-cyclopropyl- N-methylethanamine)). To our knowledge, UWA- 101 is the first dual, essentially equipotent, SERT/ DAT inhibitor to be described as showing efficacy in pre-clinical models, as an adjunct to clinically-relevant doses of L-DOPA. Specifically, when administered with L-DOPA, UWA-101, increased the proportion of ON-time that was not compromised by disabling dyskinesia in the MPTP-lesioned marmoset. However, this initial study was not designed to determine whether UWA-101 could extend the total duration of ON-time, nor the impact of UWA-101 on psychosis-like behaviours, which, like dyskinesia, may be a significant problem in the treatment of PD. The present study thus examined the effects of a wider range of dose of UWA-101, employed a longer period of assessment to enable characterisation of the duration, as well as quality of the extended ON-time, and to assess the effect of UWA-101 on psychosis-like behaviours. The reason why a balanced, in contrast to a SERT.DAT, inhibitor may not exacerbate dyskinesia can only be speculated upon. While difficult to define theoretically, it is not hard to imagine that there might be a ����sweet spot���� of relative affinities for DAT and SERT that will maximise the ability of DAT/ SERT inhibitors to increase physiological Cromakalim dopamine transmission without increasing non-physiological transmission. The following discussion will focus on aberrant dopamine release by raphestriatal Epoprostenol serotonergic axons and dopamine release by the remaining nigrostriatal fibres, though an involvement at other sites is possible. Serotonergic raphestriatal terminals have been suggested to be one site involved in the pathophysiology of L-DOPA-induced dyskinesia, as raphestriatal terminals can metabolise L-DOPA into dopamine and release it, as a ����false neurotransmitter����, in the striatum. The overspill of dopamine to nigrostriatal synapses is likely responsible for the enhancement of anti-parkinsonian benefits of L-DOPA. Raphestriatal terminals will also, via SERT, participate in dopamine re-uptake. Inhibition of SERT, by UWA-101 or S-MDMA, will enhance this overspill and thus enhance anti-parkinsonian benefits of L-DOPA. Inhibition of DAT, by UWA-101 or S-MDMA, in surviving terminals of the damaged nigrostriatal pathway will increase the possibility of interaction of dopamine with its receptors at the nigrostriatal synapse and thus further contribute to the enhancement of LDOPA anti-parkinsonian benefits.