Dopamine, but not norepinephrine or serotonin, reuptake inhibition reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.
Monoamine reuptake inhibitors that do not discriminate between the transporters for dopamine (DA), norepinephrine (NE), or 5-hydroxytryptamine (5-HT, serotonin) can reverse locomotor deficits and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. DA reuptake inhibition is presumed to be primarily responsible, but the role played by inhibition of NE and 5-HT reuptake is unknown. We now evaluate the efficacy of a range of monoamine reuptake inhibitors either alone or in combination in MPTP-treated common marmosets to determine the actions required for effective antiparkinsonian activity. Monoamine reuptake inhibitors not discriminating between the DA, NE, and 5-HT transporters [1-[1-(3,4-dichlororphenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate (BTS 74 398) and nomifensine] reversed locomotor deficits and motor disability in MPTP-treated marmosets but bupropion was without effect. The selective DA reuptake inhibitor 1-(2-(bis-(4-fluorophenyl)-methoxy)ethyl)-4-(3-phenylpropyl) piperazine) dihydrochloride (GBR 12909) also reversed these motor deficits. The relative efficacy of the compounds (BTS 74 398 > GBR 12909 > nomifensine >> bupropion) paralleled their potency in inhibiting DA uptake in vitro and in vivo. In contrast, the selective NE reuptake inhibitor nisoxetine and the 5-HT reuptake inhibitor sertraline administered alone failed to improve motor function and tended to worsen the deficits. Coadministration of nisoxetine attenuated the improvement in motor deficits produced by GBR 12909. Coadministration of sertraline also abolished the reversal of motor deficits produced by GBR 12909. Coadministration of both sertraline and nisoxetine similarly abolished the improvement of motor deficits produced by GBR 12909. Molecules possessing potent DA reuptake inhibitory activity may be useful in the treatment of the motor symptoms of Parkinson's disease. In contrast, there seems to be no role for NE or 5-HT reuptake inhibitors, and they may impair antiparkinsonian activity mediated through dopaminergic mechanisms.
Hansard
Matthew J
MJ
Neurodegenerative Disease Research Centre, Guy's, King's, and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom.
Smith
Lance A
LA
Jackson
Michael J
MJ
Cheetham
Sharon C
SC
Jenner
Peter
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002144:Callithrix; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D018759:Adrenergic Uptake Inhibitors; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors