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BEHAVIORAL PHARMACOLOGY

Dopamine Uptake Inhibitor-Induced Rotation in 6-Hydroxydopamine-Lesioned Rats Involves Both D₁ and D₂ Receptors but Is Modulated through 5-Hydroxytryptamine and Noradrenaline Receptors

Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences, King's College, London, United Kingdom (E.L.L, P.J.); and RenaSci Consultancy Ltd., BioCity, Nottingham, United Kingdom (S.C.)

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 D₁ and D₂ 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 antagonists, methysergide and metergoline, and the specific 5-HT_2C antagonist, N-desmethylclozapine, enhanced BTS 74 398-induced circling, as did the 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.

Address correspondence to: Peter Jenner, GKT School of Biomedical Sciences, Hodgkin Building, Guy's Campus, London SE1 1UL, United Kingdom. E-mail: div.pharm{at}kcl.ac.uk

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