title: The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression.
abstract: The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 431, 405 30, Gōteborg, Sweden, susannawaters@gmail.com.
authors.forename: Susanna
authors.initials: S
authors.lastname: Waters
authors.forename: Henrik
authors.initials: H
authors.lastname: Ponten
authors.forename: Malin
authors.initials: M
authors.lastname: Edling
authors.forename: Boel
authors.initials: B
authors.lastname: Svanberg
authors.forename: Daniel
authors.initials: D
authors.lastname: Klamer
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid; D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D055664:Electrochemical Techniques; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic
chemical_list: D051017:Apoptosis Regulatory Proteins; D015259:Dopamine Agents; D009124:Muscle Proteins; C491788:Nol3 protein, rat; D010880:Piperidines; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; C032727:piperidine; C483720:pridopidine; D004298:Dopamine