Ethanol acts on KCNK13 potassium channels in the ventral tegmental area to increase firing rate and modulate binge–like drinking

Abstract

Alcohol excitation of the ventral tegmental area (VTA) is important in neurobiological processes related to the development of alcoholism. The ionotropic receptors on VTA neurons that mediate ethanol-induced excitation have not been identified. Quinidine blocks ethanol excitation of VTA neurons, and blockade of two-pore potassium channels is among the actions of quinidine. Therefore two-pore potassium channels in the VTA may be potential targets for the action of ethanol. Here, we explored whether ethanol activation of VTA neurons is mediated by the twopore potassium channel KCNK13. Extracellular recordings of the response of VTA neurons to ethanol were performed in combination with knockdown of Kcnk13 using a short hairpin RNA (shRNA) in C57BL/6J mice. Real-time PCR and immunohistochemistry were used to examine expression of this channel in the VTA. Finally, the role of KCNK13 in binge-like drinking was examined in the drinking in the dark test after knockdown of the channel. Kcnk13 expression in the VTA was increased by acute ethanol exposure. Ethanol-induced excitation of VTA neurons was selectively reduced by shRNA targeting Kcnk13. Importantly, knockdown of Kcnk13 in the VTA resulted in increased alcohol drinking. These results are consistent with the idea that ethanol stimulates VTA neurons at least in part by inhibiting KCNK13, a specific two-pore potassium channel, and that KCNK13 can control both VTA neuronal activity and binge drinking. KCNK13 is a novel alcohol-sensitive molecular target and may be amenable to the development of pharmacotherapies for alcoholism treatment.

Potassium Channels and Their Potential Roles in Substance Use Disorders

“…Members of K 2P subfamilies are also differentially regulated by alcohol intake [ 50 , 80 ]. Specifically, K 2P 7.1/K cnk13 /T hik1 mRNA expression in the mouse ventral tegmental area (VTA) was upregulated by acute ethanol exposure [ 50 ] whereas mRNA levels of K 2P 1.1/K cnk1 /T wik1 , a weak inward rectifying channel, were down-regulated in the mouse cerebellum by chronic ethanol exposure [ 80 ]. Those results are interesting because Twik1 functions to set the resting membrane potential in cerebellar cells [ 87 ].…”

“…The accumulated evidence suggests that K + channels can regulate and/or facilitate the development of neuroadaptations that may be important in drug-induced progression of behaviors that are associated with the development of a SUD diagnosis [ 48 ]. Indeed, K + channel signaling appears to be impacted by exposure to various rewarding drugs that include alcohol [ 49 , 50 , 51 ], cocaine [ 52 ], methamphetamine [ 53 , 54 , 55 ], and opioids [ 56 , 57 ], morphine [ 58 , 59 ], oxycodone [ 60 ], and fentanyl [ 61 ]. Detailed effects of these drugs on potassium channels are described below.…”

Ethanol produces multiple electrophysiological effects on ventral tegmental area neurons in freely moving rats

“…Our recordings in anesthetized rats, and those of others, suggest that ethanol‐induced inhibition of DA neurons is likely to be more common in awake animals. Similar to ethanol, anesthetic agents and their metabolites can significantly alter the spontaneous firing activity of VTA neurons 18,19,39 . Anesthetics act on common molecular substrates, such as the leak potassium channels, which may mimic ethanol's actions on DA neurons in some cases 19 .…”

“…The vast majority of these studies, however, were performed under the influence of anesthesia, raising the possibility that the effect of acute ethanol administration could be different in awake, freely moving animals. Anesthetic agents, including chloral hydrate, urethane, halothane, and isoflurane, disrupt normal neural function and can significantly alter the spontaneous firing patterns of midbrain neurons 18,19 …”

A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

“…These include biochemical signaling pathways including the glutamatergic system [7], specific gene networks [8], as well as epigenetic regulatory mechanisms [6,7]. Recent observations have also suggested that potassium (K + ) channels might also be involved in modulating the compulsive intake of several drugs of abuse including alcohol [9,10], cocaine [11], methamphetamine [5], nicotine [12], and opioids [13].…”