title: Ethanol Dependence Abolishes Monoamine and GIRK (Kir3) Channel Inhibition of Orbitofrontal Cortex Excitability.
abstract: Alcohol abuse disorders are associated with dysfunction of frontal cortical areas including the orbitofrontal cortex (OFC). The OFC is extensively innervated by monoamines, and drugs that target monoamine receptors have been used to treat a number of neuropsychiatric diseases, including alcoholism. However, little is known regarding how monoamines affect OFC neuron excitability or whether this modulation is altered by chronic exposure to ethanol. In this study, we examined the effect of dopamine, norepinephrine, and serotonin on lOFC neuronal excitability in naive mice and in those exposed to chronic intermittent ethanol (CIE) treatment. All three monoamines decreased current-evoked spike firing of lOFC neurons and this action required Giα-coupled D2, α2-adrenergic, and 5HT1Areceptors, respectively. Inhibition of firing by dopamine or the D2 agonist quinpirole, but not norepinephrine or serotonin, was prevented by the GABAAreceptor antagonist picrotoxin. GABA-mediated tonic current was enhanced by dopamine or the D1 agonist SKF81297 but not quinpirole, whereas the amplitude of spontaneous IPSCs was increased by quinpirole but not dopamine. Spiking was also inhibited by the direct GIRK channel activator ML297, whereas blocking these channels with barium increased firing and eliminated the inhibitory actions of monoamines. In the presence of ML297 or the G-protein blocker GDP-β-S, DA induced a further decrease in spike firing, suggesting the involvement of a non-GIRK channel mechanism. In neurons from CIE-treated mice, spike frequency was nearly doubled and inhibition of firing by monoamines or ML297 was lost. These effects occurred in the absence of significant changes in expression of Gi/oor GIRK channel proteins. Together, these findings show that monoamines are important modulators of lOFC excitability and suggest that disruption of this process could contribute to various deficits associated with alcohol dependence.
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Sudarat
authors.initials: S
authors.lastname: Nimitvilai
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Mulholland
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Woodward
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D017982:Receptors, Biogenic Amine / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018377:Neurotransmitter Agents; D017982:Receptors, Biogenic Amine; D043562:Receptors, G-Protein-Coupled