Dopamine uptake inhibitors may provide a means of sustaining endogenous and exogenous striatal
dopamine levels in
Parkinson's disease, but most are not selective and also inhibit the
noradrenaline and
5-hydroxytryptamine (5-HT) transporters. To determine the involvement of the individual monoamine transporters in the production of motor activity, the effect of the nonselective monoamine uptake inhibitor
BTS 74 398 1-([1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio) ethanone monocitrate) and the selective
dopamine,
GBR 12909 [1-(2-(bis-(4-fluorphenyl)-methyl)ethyl)-4-(3-phenylpropyl)
piperazine) dihydrochloride],
noradrenaline (
nisoxetine), and 5-HT (
fluvoxamine) reuptake inhibitors on circling in the unilateral
6-hydroxydopamine-lesioned rat was investigated.
GBR 12909 induced ipsilateral circling, but
fluvoxamine and
nisoxetine were without effect. However, when administered with
GBR 12909,
fluvoxamine enhanced rotation, whereas
nisoxetine had no effect. The results suggest that 5-HT, but not
noradrenaline, reuptake inhibition facilitates
dopamine-mediated motor activity. To test this hypothesis,
BTS 74 398 was administered in combination with selective
dopamine, 5-HT, and
noradrenaline receptor antagonists. Both D(1) and D(2) receptor antagonists,
SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] and
raclopride, inhibited
BTS 74 398-induced circling. In contrast, the 5-HT(1A) 5-HT(1A/B) antagonists,
WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-
cyclohexane-carboxamide
maleate) and
pindolol, and the 5-HT(2A) antagonist,
ketanserin, had no effect. The nonspecific 5-HT((1/2)) antagonists,
methysergide and
metergoline, and the specific 5-HT(2C) antagonist,
N-desmethylclozapine, enhanced
BTS 74 398-induced circling, as did the alpha(2)-
adrenoceptor antagonist
idazoxan. Overall, the data suggest that inhibition of the 5-HT and
noradrenaline transporters modulate
dopamine uptake inhibitor-mediated motor activity. However, the mechanism of this interaction is complex, involving opposing effects of
noradrenaline and 5-HT agonism and antagonism.