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Dopamine uptake inhibitor-induced rotation in 6-hydroxydopamine-lesioned rats involves both D-1 and D-2 receptors but is modulated through 5-hydroxytryptamine and noradrenaline receptors

Lane, Emma Louise, Cheetham, S. and Jenner, P. 2005. Dopamine uptake inhibitor-induced rotation in 6-hydroxydopamine-lesioned rats involves both D-1 and D-2 receptors but is modulated through 5-hydroxytryptamine and noradrenaline receptors. Journal of Pharmacology and Experimental Therapeutics 312 (3) , pp. 1124-1131. 10.1124/jpet.104.076554

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Abstract

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-HT1A 5-HT1A/B antagonists, WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexane-carboxamide maleate) and pindolol, and the 5-HT2A antagonist, ketanserin, had no effect. The nonspecific 5-HT½ antagonists, methysergide and metergoline, and the specific 5-HT2C antagonist, N-desmethylclozapine, enhanced BTS 74 398-induced circling, as did the α2-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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: HighWire Press
ISSN: 0022-3565
Last Modified: 04 Jun 2017 02:57
URI: http://orca-mwe.cf.ac.uk/id/eprint/14614

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