TY - JOUR
T1 - Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons
T2 - a sensitive target for ethanol
AU - Maguire, Edward P.
AU - Mitchell, Elizabeth A.
AU - Greig, Scott J.
AU - Corteen, Nicole
AU - Balfour, David J. K.
AU - Swinny, Jerome D.
AU - Lambert, Jeremy J.
AU - Belelli, Delia
PY - 2014/4
Y1 - 2014/4
N2 - 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 behavioural actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterise DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory 'phasic' postsynaptic 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 behaviourally-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.
AB - 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 behavioural actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterise DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory 'phasic' postsynaptic 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 behaviourally-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.
KW - glycine
KW - Tonic inhibition
KW - Alcohol
KW - serotonin dorsal raphe
U2 - 10.1038/npp.2013.326
DO - 10.1038/npp.2013.326
M3 - Article
C2 - 24264816
SN - 0893-133X
VL - 39
SP - 1232
EP - 1244
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 5
ER -
