Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula

Alcohol use disorders (AUDs) and anxiety disorders (ADs) are often seen concurrently, but their underlying cellular basis is unclear. For unclear reasons, the lateral habenula (LHb), a key brain region involved in the pathophysiology of ADs, becomes hyperactive after ethanol withdrawal. M-type K+ channels (M-channels), important regulators of neuronal activity, are abundant in the LHb, yet little is known about their role in AUDs and associated ADs. We report here that in rats at 24 h withdrawal from systemic ethanol administration (either by intraperitoneal injection, 2 g/kg, twice/day, for 7 days; or intermittent drinking 20% ethanol in a two-bottle free choice protocol for 8 weeks), the basal firing rate and the excitability of LHb neurons in brain slices was higher, whereas the amplitude of medium afterhyperpolarization and M-type K+ currents were smaller, when compared to ethanol naive rats. Concordantly, M-channel blocker (XE991)-induced increase in the spontaneous firing rate in LHb neurons was smaller. The protein expression of M-channel subunits, KCNQ2/3 in the LHb was also smaller. Moreover, anxiety levels (tested in open field, marble burying, and elevated plus maze) were higher, which were alleviated by LHb inhibition either chemogenetically or by local infusion of the M-channel opener, retigabine. Intra-LHb infusion of retigabine also reduced ethanol consumption and preference. These findings reveal an important role of LHb M-channels in the expression of AUDs and ADs, and suggest that the M-channels could be a potential therapeutic target for alcoholics.

[1]  Kyle S. Smith,et al.  Dreadds: Use and Application in Behavioral Neuroscience Section 1: Advantages for Behavioral Neuroscience Dreadds Involve the Use of Receptor Proteins Derived from Targeted Mutagenesis of Endogenous G-protein Coupled Receptor , 2022 .

[2]  Laura B. Ferguson,et al.  The synaptoneurosome transcriptome: a model for profiling the emolecular effects of alcohol , 2014, The Pharmacogenomics Journal.

[3]  P. Delmas,et al.  Pathways modulating neural KCNQ/M (Kv7) potassium channels , 2005, Nature Reviews Neuroscience.

[4]  P. Albert,et al.  Transcriptional dys-regulation in anxiety and major depression: 5-HT1A gene promoter architecture as a therapeutic opportunity. , 2014, Current pharmaceutical design.

[5]  R. Veh,et al.  Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices , 2011, Neuroscience.

[6]  R. Pobbe,et al.  The dorsal raphe nucleus exerts opposed control on generalized anxiety and panic-related defensive responses in rats , 2003, Behavioural Brain Research.

[7]  D. Ciraulo,et al.  The Kv7 potassium channel activator retigabine decreases alcohol consumption in rats , 2014, The American journal of drug and alcohol abuse.

[8]  S. D. Moore,et al.  Ethanol diminishes a voltage-dependent K+ current, the M-current, in CA1 hippocampal pyramidal neurons in vitro , 1990, Brain Research.

[9]  James J. L. Hodge,et al.  KCNQ Channels Show Conserved Ethanol Block and Function in Ethanol Behaviour , 2012, PloS one.

[10]  S. Montgomery,et al.  Prevalence of anxiety disorders comorbidity in bipolar depression, unipolar depression and dysthymia. , 1997, Journal of affective disorders.

[11]  F. Graeff,et al.  Role of 5-HT in stress, anxiety, and depression , 1996, Pharmacology Biochemistry and Behavior.

[12]  K. Krnjević,et al.  Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor‐mediated activation of lateral habenula neurons , 2017, Addiction biology.

[13]  M. Nicolelis,et al.  Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors , 2009, Neuron.

[14]  R. Sinha.  How does stress increase risk of drug abuse and relapse? , 2001, Psychopharmacology.

[15]  J. Storm,et al.  Kv7/KCNQ/M‐channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release , 2006, The Journal of physiology.

[16]  H. Okamoto,et al.  Hyperactivation of the habenula as a link between depression and sleep disturbance , 2013, Front. Hum. Neurosci..

[17]  D. De Ridder,et al.  Anterior Cingulate Implant for Obsessive-Compulsive Disorder. , 2017, World neurosurgery.

[18]  R. Wise,et al.  Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. , 2008, Alcoholism, clinical and experimental research.

[19]  F. J. White,et al.  Whole-Cell Plasticity in Cocaine Withdrawal: Reduced Sodium Currents in Nucleus Accumbens Neurons , 1998, The Journal of Neuroscience.

[20]  P. Baldwin,et al.  The Role of the Habenula in Nicotine Addiction. , 2011, Journal of addiction research & therapy.

[21]  I. Sakata,et al.  Molecular identification of GHS-R and GPR38 in Suncus murinus , 2012, Peptides.

[22]  G. Koob,et al.  CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat , 2005, Psychopharmacology.

[23]  Lezanne Ooi,et al.  Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury , 2011, PAIN®.

[24]  K. Junghanns,et al.  The course of anxiety, depression and drinking behaviours after completed detoxification in alcoholics with and without comorbid anxiety and depressive disorders. , 2001, Alcohol and alcoholism.

[25]  R. Malinow,et al.  βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression , 2013, Science.

[26]  M. Roberto,et al.  The Central Amygdala as an Integrative Hub for Anxiety and Alcohol Use Disorders , 2015, Biological Psychiatry.

[27]  M. Brodie,et al.  Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. , 2007, Journal of neurophysiology.

[28]  R. Pobbe,et al.  Involvement of the lateral habenula in the regulation of generalized anxiety- and panic-related defensive responses in rats. , 2008, Life sciences.

[29]  F. Meye,et al.  Synaptic and cellular profile of neurons in the lateral habenula , 2013, Front. Hum. Neurosci..

[30]  S. Handley,et al.  Evaluation of marble-burying behavior as a model of anxiety , 1991, Pharmacology Biochemistry and Behavior.

[31]  Stefan Boehm,et al.  Distribution of M-channel subunits KCNQ2 and KCNQ3 in rat hippocampus , 2011, NeuroImage.

[32]  Antônio C. Roque-da-Silva,et al.  Anxiety-like behavior in rats: a computational model , 2000, Neural Networks.

[33]  B. Roth,et al.  Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand , 2007, Proceedings of the National Academy of Sciences.

[34]  R. Wise.  Voluntary ethanol intake in rats following exposure to ethanol on various schedules , 2004, Psychopharmacologia.

[35]  Johan F. Storm,et al.  Kv 7 / KCNQ / M and HCN / h , but not KCa 2 / SK channels , contribute to the somatic medium after-hyperpolarization and excitability control in CA 1 hippocampal pyramidal cells , 2005 .

[36]  D. Joel,et al.  Current animal models of obsessive compulsive disorder: an update , 2012, Neuroscience.

[37]  S. Pandey,et al.  The decreased phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein in the central amygdala acts as a molecular substrate for anxiety related to ethanol withdrawal in rats. , 2003, Alcoholism, clinical and experimental research.

[38]  Z. Wang,et al.  Ethanol-induced neurodegeneration in NRSF/REST neuronal conditional knockout mice , 2011, Neuroscience.

[39]  B. Robertson,et al.  Transcriptional Control of KCNQ Channel Genes and the Regulation of Neuronal Excitability , 2010, The Journal of Neuroscience.

[40]  Samuel D. Dolzani,et al.  Activation of a Habenulo–Raphe Circuit Is Critical for the Behavioral and Neurochemical Consequences of Uncontrollable Stress in the Male Rat , 2016, eNeuro.

[41]  J. Wolpaw,et al.  Operantly conditioned motoneuron plasticity: possible role of sodium channels. , 1995, Journal of neurophysiology.

[42]  Lesions of the Lateral Habenula Increase Voluntary Ethanol Consumption and Operant Self-Administration, Block Yohimbine-Induced Reinstatement of Ethanol Seeking, and Attenuate Ethanol-Induced Conditioned Taste Aversion , 2014, PloS one.

[43]  M. Tateno,et al.  Lithium-induced suppression of transcription repressor NRSF/REST: effects on the dysfunction of neuronal differentiation by ethanol. , 2008, European journal of pharmacology.

[44]  S. Pandey,et al.  Central and Medial Amygdaloid Brain-Derived Neurotrophic Factor Signaling Plays a Critical Role in Alcohol-Drinking and Anxiety-Like Behaviors , 2006, The Journal of Neuroscience.

[45]  James S Trimmer,et al.  Subcellular Localization of K+ Channels in Mammalian Brain Neurons: Remarkable Precision in the Midst of Extraordinary Complexity , 2015, Neuron.

[46]  Pengyue Zhang,et al.  D1-like dopamine receptor dysfunction in the lateral habenula nucleus increased anxiety-like behavior in rat , 2017, Neuroscience.

[47]  M. Tateno,et al.  Implication of increased NRSF/REST binding activity in the mechanism of ethanol inhibition of neuronal differentiation , 2006, Journal of Neural Transmission.

[48]  Hua Hu,et al.  Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after‐hyperpolarization and excitability control in CA1 hippocampal pyramidal cells , 2005, The Journal of physiology.

[49]  J. Ye,et al.  Chronic intermittent voluntary alcohol drinking induces hyperalgesia in Sprague-Dawley rats. , 2015, International journal of physiology, pathophysiology and pharmacology.

[50]  J. Kotlinska,et al.  Enkephalin analog, cyclo[N(ε),N(β)-carbonyl-D-Lys(2),Dap(5)] enkephalinamide (cUENK6), inhibits the ethanol withdrawal-induced anxiety-like behavior in rats. , 2015, Alcohol.

[51]  W. Mcbride.  Central nucleus of the amygdala and the effects of alcohol and alcohol-drinking behavior in rodents , 2002, Pharmacology Biochemistry and Behavior.

[52]  Ryoji Amamoto,et al.  Excessive alcohol consumption is blocked by glial cell line-derived neurotrophic factor. , 2009, Alcohol.

[53]  D. Overstreet,et al.  Modulation of ethanol withdrawal-induced anxiety-like behavior during later withdrawals by treatment of early withdrawals with benzodiazepine/gamma-aminobutyric acid ligands. , 2005, Alcoholism, clinical and experimental research.

[54]  Vincent Seutin,et al.  Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS , 2008, The Journal of physiology.

[55]  L. Descarries,et al.  Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion , 1982, Brain Research.

[56]  Benjamin Rusak,et al.  The role of lateral habenula–dorsal raphe nucleus circuits in higher brain functions and psychiatric illness , 2015, Behavioural Brain Research.

[57]  N. Coimbra,et al.  Differential involvement of dorsal raphe subnuclei in the regulation of anxiety- and panic-related defensive behaviors , 2012, Neuroscience.

[58]  Christophe D. Proulx,et al.  Reward processing by the lateral habenula in normal and depressive behaviors , 2014, Nature Neuroscience.

[59]  Andreas Lüthi,et al.  Neuronal circuits for fear and anxiety , 2015, Nature Reviews Neuroscience.

[60]  Elissa J Chesler,et al.  Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption , 2016, Addiction biology.

[61]  D. Strøbæk,et al.  Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal Kv7 Channels , 2005, Journal of Pharmacology and Experimental Therapeutics.

[62]  Christophe D. Proulx,et al.  Synaptic potentiation onto habenula neurons in learned helplessness model of depression , 2010, Nature.

[63]  J. Ye,et al.  High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats , 2016, The international journal of neuropsychopharmacology.

[64]  D. A. Brown,et al.  Molecular correlates of the M‐current in cultured rat hippocampal neurons , 2002, The Journal of physiology.

[65]  Stephen G Waxman,et al.  Regulating excitability of peripheral afferents: emerging ion channel targets , 2014, Nature Neuroscience.

[66]  J. Ye,et al.  Blockade of GABAA receptors in the paraventricular nucleus of the hypothalamus attenuates voluntary ethanol intake and activates the hypothalamic–pituitary–adrenocortical axis , 2011, Addiction biology.

[67]  M. Sailer,et al.  Primary carnitine deficiency: adult onset lipid storage myopathy with a mild clinical course , 2004, Journal of Clinical Neuroscience.

[68]  A. Ettenberg,et al.  Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration , 2016, Behavioural Brain Research.

[69]  O. Hikosaka.  The habenula: from stress evasion to value-based decision-making , 2010, Nature Reviews Neuroscience.

[70]  E. Cooper,et al.  Channel-anchored Protein Kinase CK2 and Protein Phosphatase 1 Reciprocally Regulate KCNQ2-containing M-channels via Phosphorylation of Calmodulin* , 2014, The Journal of Biological Chemistry.

[71]  P. Pedarzani,et al.  Molecular determinants of Ca2+‐dependent K+ channel function in rat dorsal vagal neurones , 2000, The Journal of physiology.

[72]  S. Hedden,et al.  Past Year Mental Disorders among Adults in the United States: Results from the 2008–2012 Mental Health Surveillance Study , 2014 .

[73]  F. Meye,et al.  The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview , 2014, The European journal of neuroscience.

[74]  D. Lowenstein,et al.  Hippocampal Heterotopia Lack Functional Kv4.2 Potassium Channels in the Methylazoxymethanol Model of Cortical Malformations and Epilepsy , 2001, The Journal of Neuroscience.

[75]  Russell S. Ray,et al.  Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors. , 2015, Cell reports.

[76]  B S Brown,et al.  KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. , 1998, Science.

[77]  P. Kushner,et al.  Family of human neuronal external surface epitopes defined by torpedo monoclonal antibodies , 1990, Journal of neuroscience research.

[78]  Donna J. Calu,et al.  Intrinsic plasticity: an emerging player in addiction , 2015, Nature Reviews Neuroscience.

[79]  Hiroaki Misonou,et al.  Homeostatic Regulation of Neuronal Excitability by K+ Channels in Normal and Diseased Brains , 2010, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.