title: Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons: a sensitive target for ethanol.
abstract: Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory 'phasic' post-synaptic currents mediated primarily by synaptic GABAA receptors (GABAAR) and, to a lesser extent, by synaptic glycine receptors (GlyR). In addition to such phasic transmission mediated by the vesicular release of neurotransmitter, the activity of certain neurons may be governed by a 'tonic' conductance resulting from ambient GABA activating extrasynaptic GABAARs. However, for DR neurons extrasynaptic GABAARs exert only a limited influence. By contrast, we report that unusually the GlyR antagonist strychnine reveals a large tonic conductance mediated by extrasynaptic GlyRs, which dominates DR inhibition. In agreement, for DR neurons strychnine increases their input resistance, induces membrane depolarization, and consequently augments their excitability. Importantly, this glycinergic conductance is greatly enhanced in a strychnine-sensitive fashion, by behaviorally relevant ethanol concentrations, by drugs used for the treatment of alcohol withdrawal, and by taurine, an ingredient of certain 'energy drinks' often imbibed with ethanol. These findings identify extrasynaptic GlyRs as critical regulators of DR excitability and a novel molecular target for ethanol.
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, UK.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Maguire
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mitchell
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, UK.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Greig
authors.affiliation: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Corteen
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, UK.
authors.forename: David J K
authors.initials: DJ
authors.lastname: Balfour
authors.affiliation: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: Jerome D
authors.initials: JD
authors.lastname: Swinny
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, UK.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, UK.
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005998:Glycine / Q000378:metabolism; D018684:Glycine Agents / Q000494:pharmacology; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology; D000099247:Taurine Transporters
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D005998:Glycine; D018684:Glycine Agents; D050487:Glycine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D013331:Strychnine; D000099247:Taurine Transporters; C493267:Slc6a9 protein, mouse