title: The dopaminergic stabilizer pridopidine increases neuronal activity of pyramidal neurons in the prefrontal cortex.
abstract: The dopaminergic stabilizer pridopidine demonstrates state-dependent effects on locomotor activity, counteracting both hypo- and hyperactivity in rats. Pridopidine has been shown to display both functional dopamine D2 receptor antagonist properties and increase in biomarkers associated with NMDA-mediated glutamate transmission in the frontal cortex. To further characterise the effects of pridopidine on prefrontal cortex (PFC) neurons, a series of in vivo electrophysiological studies were performed in urethane-anaesthetised rats. Pridopidine, administered at doses from 10 to 60 mg/kg (i.v.), dose dependently increased pyramidal cell firing in the majority of the neurons tested. Pridopidine induced a significant increase of 162 % in mean firing activity of PFC neurons, versus initial basal firing activity as the cumulative dose of 30 mg/kg, i.v., was administered. This enhancement of activity was due to increased firing frequency of already spontaneously active neurons, rather than an increase in population activity. The increase was partially reversed or prevented by a sub-threshold dose of the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg, i.v.). Microiontophoretic application of pridopidine had only moderate activating effects. The selective dopamine D1 receptor agonist A-68930 also had limited effects when administered by microiontophoretic application, but exerted a dose dependent (0.2-3 mg/kg, i.v.) activation of firing in the majority of neurons tested (10/16). However, inhibition of firing by systemic administration of A-68930 was also observed in a subgroup of neurons (6/16). Both activation and inhibition of firing induced by systemic administration of A-68930 were reversed by the systemic administration of SCH23390. The present data suggests that pridopidine enhances pyramidal cell firing via an indirect dopamine D1 receptor-mediated mechanism. These effects of pridopidine may serve to strengthen the cortico-striatal communication and to improve motor control in Huntington's disease for which pridopidine is currently in development.
authors.affiliation: De Montfort University, Leicester School of Pharmacy, The Gateway, Leicester, LE1 9BH, UK. bgronier@dmu.ac.uk
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gronier
authors.forename: Susanna
authors.initials: S
authors.lastname: Waters
authors.forename: Henrik
authors.initials: H
authors.lastname: Ponten
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D015259:Dopamine Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors
chemical_list: D001552:Benzazepines; D002839:Chromans; D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010880:Piperidines; D017447:Receptors, Dopamine D1; C534628:SCH 23390; C065380:A 68930; C483720:pridopidine; D006220:Haloperidol