Search

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of L-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with L-DOPA, UWA-121 extended duration of ON-time when compared to L-DOPA/vehicle treatment (by 40%, P < 0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P < 0.05) and ON-time without psychosis-like behaviours when compared to L-DOPA/vehicle treatment (by 345%, P < 0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 μM) and, in combination with L-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance L-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD., (Copyright © 2014. Published by Elsevier Ltd.)

Long-term L-DOPA treatment for Parkinson's disease (PD) is limited by motor complications, particularly L-DOPA-induced dyskinesia (LID). A therapy with the ability to ameliorate LID without reducing anti-parkinsonian benefit would be of great value. We assessed the ability of TC-8831, an agonist at nicotinic acetylcholine receptors (nAChR) containing α6β2/α4β2 subunit combinations, to provide such benefits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) lesioned macaques with established LID. Animals were treated orally for consecutive 14-day periods with twice-daily vehicle (weeks 1-2) or TC-8831 (0.03, 0.1 or 0.3 mg/kg, weeks 3-8). L-DOPA was also administered, once-daily, (weeks 1-12, median-dose 30 mg/kg, p.o.). For the following two-weeks (weeks 9-10), TC-8831 was washed out, while once-daily L-DOPA treatment was maintained. The effects of once-daily amantadine (3 mg/kg, p.o.) were then assessed over weeks 11-12. LID, parkinsonism, duration and quality of ON-time were assessed weekly by a neurologist blinded to treatment. TC-8831 reduced the duration of 'bad' ON-time (ON-time with disabling dyskinesia) by up to 62% and decreased LID severity (median score 18 cf. 34 (vehicle), 0.1 mg/kg, 1-3 h period). TC-8831 also significantly reduced choreiform and dystonic dyskinesia (median scores 6 and 31 cf. 19 and 31 respectively (vehicle), both 0.03 mg/kg, 1-3 h). At no time did TC-8831 treatment result in a reduction in anti-parkinsonian benefit of L-DOPA. By comparison, amantadine also significantly reduced dyskinesia and decreased 'bad' ON-time (up to 61%) but at the expense of total ON-time (reduced by up to 23%). TC-8831 displayed robust anti-dyskinetic actions and improved the quality of ON-time evoked by L-DOPA without any reduction in anti-parkinsonian benefit., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of L-3,4-dihydroxyphenylalanine (L-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single L-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma L-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients., Methods: We administered acute challenges of L-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of L-DOPA using high-performance liquid chromatography-mass spectrometry/mass spectrometry., Results: The maximal plasma concentration of L-DOPA (C(max)) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (t(max)). Half-life was 58.8 ± 22.7 min. L-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF., Conclusions: Although therapeutically-active doses of L-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to L-DOPA C(max) similar to those achieved with 200 mg L-DOPA in clinic. L-DOPA t(max) and half-life are also similar to those reported in human., (Copyright © 2012. Published by Elsevier Ltd.)

Recent investigations have demonstrated that prenatal 3,4-methylenedeoxymethamphetamine (MDMA; ecstasy) exposure in rats results in significant and persistent changes in the developing brain. However, no published pharmacokinetic studies exist demonstrating that MDMA administered during pregnancy passes to the fetal compartment. This leaves open the question whether MDMA is directly acting on the fetal brain to produce the observed changes in previous studies, or whether such effects are an indirect result of MDMA administration to the pregnant dam. Therefore, pregnant rats were administered a single dose of MDMA (15 mg/kg, subcutaneous) at embryonic day 14 (E14) and the levels of MDMA and its metabolite 3,4-methylenedioxyamphetamine (MDA) were quantified in maternal plasma, amniotic fluid, and fetal brain over 8 h by HPLC. The time course of MDMA and MDA metabolism was reliable and reproducible in all tissues. There was a strong correlation between fetal amniotic fluid and fetal brain suggesting that amniotic fluid could be used to reliably estimate fetal brain levels without directly utilizing fetal brain tissue. These data also provide a framework for subsequent in vitro cell culture studies using biologically relevant MDMA doses.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) use has risen among women of childbearing age. Consequently, there is a substantial risk for fetal exposure from women who are, or become pregnant while abusing MDMA. However, attempts to demonstrate that prenatal MDMA results in neurochemical alterations in rat models have failed. MDMA administration to neonatal rats (third trimester equivalent) results in significant and persistent neurochemical and behavioral alterations, yet human epidemiologic data suggest that the vast majority of prenatal exposure is limited to the first trimester. The following study was conducted to reexamine the potential for prenatal MDMA administration to produce lasting postnatal neurochemical and behavioral alterations using a new rodent model. Pregnant rats were administered twice-daily injections of MDMA (15 mg/kg sc) or saline from embryonic days (E) 14-20. Prenatally exposed pups were examined on postnatal days (P) 3 and 21. At P3, MDMA offspring showed reductions in the dopamine metabolite homovanillic acid which persisted through P21, along with reductions in the serotonin (5-HT) metabolite, 5-HIAA. Prenatally exposed MDMA animals at P21 also had reduced dopamine and 5-HT turnover in the nucleus accumbens. Increases in tyrosine hydroxylase fiber density were found in the frontal cortex, striatum and nucleus accumbens of MDMA animals. In addition, prenatal MDMA significantly increased locomotor activity of P21 pups in a 20-min novel cage environment. These findings provide the first evidence of lasting neurochemical and behavioral alterations following prenatal MDMA. Further investigation is warranted to elucidate possible mechanisms of action and to monitor children gestationally exposed to MDMA.