title: Co-administration of the Dopaminergic Stabilizer Pridopidine and Tetrabenazine in Rats.
abstract: BACKGROUND
  The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission.
  
  
  OBJECTIVE
  To investigate pharmacological interactions between pridopidine and tetrabenazine.
  
  
  METHODS
  Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison.
  
  
  RESULTS
  Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine.
  
  
  CONCLUSIONS
  Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy.
authors.affiliation: Department of Pharmacology, Gothenburg University, Gothenburg, Sweden Integrative Research Laboratories AB, A Wallgrens Backe, Gothenburg, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Waters
authors.affiliation: Department of Pharmacology, Gothenburg University, Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ponten
authors.affiliation: Department of Pharmacology, Gothenburg University, Gothenburg, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Klamer
authors.affiliation: Integrative Research Laboratories AB, A Wallgrens Backe, Gothenburg, Sweden.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D010880:Piperidines; C483720:pridopidine; D004298:Dopamine; D013747:Tetrabenazine
keywords: Huntington's disease; dopaminergic stabilizer; haloperidol; locomotor activity; pridopidine; tetrabenazine