title: The dopaminergic stabilizer pridopidine decreases expression of L-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model.
abstract: Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (L-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.5mg/kg L-DOPA; L-DOPA + 25 μmol/kg pridopidine; or L-DOPA + 25 μmol/kg (-)-OSU6162-a prototype dopaminergic stabilizer used previously in 6-OHDA hemi-lesion models. Animals were treated for 7, 14 or 21 days, and locomotor activity and ex vivo brain tissue neurochemistry analysed. In agreement with previous studies, L-DOPA sensitised the motor response, producing significantly more contralateral rotations than vehicle (P<0.05). Concomitant administration of pridopidine and L-DOPA significantly decreased the number of L-DOPA-induced contralateral rotations on day 7, 14 and 21 (P<0.05 versus L-DOPA alone), while still allowing a beneficial locomotor stimulant effect of L-DOPA. Concomitant pridopidine also reduced L-DOPA-induced rotation asymmetry (P<0.05 versus L-DOPA alone) and had no adverse effects on distance travelled. Brain neurochemistry was generally unaffected in all treatments groups. In conclusion, pridopidine shows potential for reducing motor complications of L-DOPA in Parkinson's disease and further testing is warranted.
authors.affiliation: NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden. henrik.ponten@neurosearch.se
authors.forename: Henrik
authors.initials: H
authors.lastname: Ponten
authors.forename: Johan
authors.initials: J
authors.lastname: Kullingsjö
authors.forename: Clas
authors.initials: C
authors.lastname: Sonesson
authors.forename: Susanna
authors.initials: S
authors.lastname: Waters
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
authors.forename: Joakim
authors.initials: J
authors.lastname: Tedroff
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013997:Time Factors
chemical_list: D015259:Dopamine Agents; D010880:Piperidines; D007980:Levodopa; D016627:Oxidopamine; C483720:pridopidine; D004298:Dopamine