title: Antipsychotic-like effect of retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ potassium channel opener, via modulation of mesolimbic dopaminergic neurotransmission.
abstract: Dopaminergic (DAergic) neurons in the ventral tegmental area express both KCNQ2 and KCNQ4 channels, which opening is expected to decrease neuronal excitability via neuronal hyper-polarization. Because psychotic symptoms are believed to be associated with an increased excitability of dopamine (DA) cells in the mesencephalon, KCNQ channels might represent a new potential target for the treatment of psychosis. The aim of our study was to investigate the antipsychotic-like potential of KCNQ channel opening via modulation of neuronal activity within the mesolimbic DAergic system. We report that retigabine [N-(2-amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ opener, dose-dependently reduced basal DA firing rate and more potently suppressed burst firing activity in the ventral tegmental area, whereas XE-991 [10,10-bis(pyridinylmethyl)-9(10H)-anthracenone], a selective KCNQ blocker, induced opposite effects. In addition, retigabine prevented d-amphetamine-induced DA efflux in the nucleus accumbens and d-amphetamine-induced locomotor hyperactivity. In contrast, XE-991 potentiated both the locomotor hyperactivity and DA efflux evoked by d-amphetamine. These data strongly suggest that the activation of KCNQ channels attenuates DAergic neurotransmission in the mesolimbic system, particularly in conditions of excessive DAergic activity. In a model predictive of antipsychotic activity, the conditioned avoidance response paradigm, retigabine was found to inhibit avoidance responses, an effect blocked by coadministration of XE-991. Furthermore, retigabine was found to significantly inhibit the hyperlocomotor response to a phencyclidine (PCP) challenge in PCP-sensitized animals, considered as a disease model for schizophrenia. Taken together, our studies provide evidence that KCNQ channel openers represent a potential new class of antipsychotics.
authors.affiliation: Department of Neurophysiology, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Florence
authors.initials: F
authors.lastname: Sotty
authors.forename: Trine
authors.initials: T
authors.lastname: Damgaard
authors.forename: Liliana P
authors.initials: LP
authors.lastname: Montezinho
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.forename: Christina K
authors.initials: CK
authors.lastname: Olsen
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.forename: Henriette
authors.initials: H
authors.lastname: Husum
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D010655:Phenylenediamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D014150:Antipsychotic Agents; D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; C101866:ezogabine; D004298:Dopamine