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 G-coupled D2, α2-adrenergic, and 5HT receptors, respectively. Inhibition of firing by dopamine or the D2 agonist quinpirole, but not norepinephrine or serotonin, was prevented by the GABA receptor 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 G or 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.

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

“…PL pyramidal excitability and spike firing is modulated by activity of G protein-gated inwardly rectifying K + (GIRK/Kir3) channels which produce a slow hyperpolarizing current that acts as a neuronal "off switch" (41)(42)(43)(44). GIRK channels are the primary postsynaptic downstream effector for inhibitory metabotropic receptors, including perisomatic GABAB receptor (GABAB)a major target of local GABA neurons (45,46).…”

Chronic intermittent ethanol exposure selectively alters the expression of Gα subunit isoforms and RGS subtypes in rat prefrontal cortex

“…On the other hand, changes in GPCR function following ethanol exposure can also be independent of Gα subunit expression. For example, CIE profoundly reduces dopamine D2 receptor-mediated activation of GIRK channels in the absence of significant alterations in Gαi/o subunit expression in mouse orbitofrontal cortex (Nimitvilai et al ., 2017). In this later instance, altered GPCR function following CIE could be due to changes in Gα-interacting proteins such as RGS proteins; this mechanism has not been extensively investigated in the alcohol field.…”

“…These changes likely mediate adaptive changes in neuronal function in response to alcohol exposure. Animal models of alcohol abuse have shown complex changes in the PFC, including functions of many G-protein coupled receptors (GPCRs) and voltage-gated ion channels (Johnson & Lovinger, 2016, Nimitvilai et al , 2017), which interact with modulatory, heterotrimeric G-protein signaling pathways. G-proteins are divided into four major subfamilies based on Gα-subunit sequence homology and their specific interactions with downstream effector proteins: the Gαi/o family inhibits adenylyl cyclase, the Gαs family stimulates adenylyl cyclase, the Gαq/11 family stimulates phospholipase Cβ, and the Gα12/13 family activates rhoGEP and other effectors (Milligan, 1993, Nurnberg et al , 1995).…”

A randomized controlled study of the effect of ifenprodil on alcohol use in patients with alcohol dependence

“…G i/o proteins are activated by neurotransmitters at various G i/o protein‐coupled receptors, including M 2 muscarinic, opioid, α2‐adrenergic, γ‐aminobutyric acid‐B, D 2 dopaminergic, and 5‐HT 1A serotonergic receptors. G protein βγ subunits dissociate from G protein α subunits to open GIRK channels . The opening of GIRK channels hyperpolarizes the cell membrane to modulate neuronal excitability.…”

“…G protein bc subunits dissociate from G protein a subunits to open GIRK channels. [5][6][7] The opening of GIRK channels hyperpolarizes the cell membrane to modulate neuronal excitability. Ethanol has been found to directly open GIRK channels.…”