title: The anti-epileptic actions of neuropeptide Y in the hippocampus are mediated by Y and not Y receptors.
abstract: Neuropeptide Y (NPY) potently inhibits glutamate release and seizure activity in rodent hippocampus in vitro and in vivo, but the nature of the receptor(s) mediating this action is controversial. In hippocampal slices from rats and several wild-type mice, a Y2-preferring agonist mimicked, and the Y2-specific antagonist BIIE0246 blocked, the NPY-mediated inhibition both of glutamatergic transmission and of epileptiform discharges in two different slice models of temporal lobe epilepsy, stimulus train-induced bursting (STIB) and 0-Mg2+ bursting. Whereas Y5 receptor-preferring agonists had small but significant effects in vitro, they were blocked by BIIE0246, and a Y5 receptor-specific antagonist did not affect responses to any agonist tested in any preparation. In slices from mice, NPY was without effect on evoked potentials or in either of the two slice seizure models. In vivo, intrahippocampal injections of Y2- or Y5-preferring agonists inhibited seizures caused by intrahippocampal kainate, but again the Y5 agonist effects were insensitive to a Y5 antagonist. Neither Y2- nor Y5-preferring agonists affected kainate seizures in mice. A Y5-specific antagonist did not displace the binding of two different NPY ligands in WT or mice, whereas all NPY binding was eliminated in the mouse. Thus, we show that Y2 receptors alone mediate all the anti-excitatory actions of NPY seen in the hippocampus, whereas our findings do not support a role for Y5 receptors either in vitro or in vivo. The results suggest that agonists targeting the Y2 receptor may be useful anticonvulsants.
authors.affiliation: Department of Pharmacology, University of Alberta. Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Bouchaïb
authors.initials: B
authors.lastname: El Bahh
authors.forename: Silvia
authors.initials: S
authors.lastname: Balosso
authors.forename: Trevor
authors.initials: T
authors.lastname: Hamilton
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
authors.forename: Günther
authors.initials: G
authors.lastname: Sperk
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007608:Kainic Acid; D008274:Magnesium / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000494:pharmacology*; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D013569:Synapses / Q000187:drug effects / Q000502:physiology
chemical_list: D000927:Anticonvulsants; D001552:Benzazepines; D018690:Excitatory Amino Acid Agonists; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C100568:neuropeptide Y5 receptor; D001120:Arginine; D008274:Magnesium; C403256:BIIE 0246; D007608:Kainic Acid