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Persons at risk for developing alcohol use disorder (AUD) differ in their sensitivity to acute alcohol intoxication. Alcohol effects are complex and thought to depend on multiple mechanisms. Here, we explored whether acid-sensing ion channels (ASICs) might play a role. We tested ASIC function in transfected CHO cells and amygdala principal neurons, and found alcohol potentiated currents mediated by ASIC1A homomeric channels, but not ASIC1A/2 A heteromeric channels. Supporting a role for ASIC1A in the intoxicating effects of alcohol in vivo, we observed marked alcohol-induced changes on local field potentials in basolateral amygdala, which differed significantly in Asic1a–/– mice, particularly in the gamma, delta, and theta frequency ranges. Altered electrophysiological responses to alcohol in mice lacking ASIC1A, were accompanied by changes in multiple behavioral measures. Alcohol administration during amygdala-dependent fear conditioning dramatically diminished context and cue-evoked memory on subsequent days after the alcohol had cleared. There was a significant alcohol by genotype interaction. Context- and cue-evoked memory were notably worse in Asic1a–/– mice. We further examined acute stimulating and sedating effects of alcohol on locomotor activity, loss of righting reflex, and in an acute intoxication severity scale. We found loss of ASIC1A increased the stimulating effects of alcohol and reduced the sedating effects compared to wild-type mice, despite similar blood alcohol levels. Together these observations suggest a novel role for ASIC1A in the acute intoxicating effects of alcohol in mice. They further suggest that ASICs might contribute to intoxicating effects of alcohol and AUD in humans.
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We would like to thank Dr. Youngcho Kim for assistance in in vivo electrophysiology techniques.
JAW was supported by NIH National Institute of Mental Health grant R01MH113325, NIH National Institute of Drug Abuse grant R01DA052953, the Roy J. Carver Charitable Trust, the Roy J. Carver Chair, a U.S. Department of Veterans Affairs Merit Review Award, and the U.S. Department of Veterans Affairs. GISH was supported by NIH National Institute of Neurological Disorders and Stroke training grant T32NS007421, NIH National Institute of General Medical Sciences training grant T32GM067795, and the University of Iowa Ballard and Seashore Dissertation Fellowship. ACC was supported by NIH National Institute of Mental Health training grant T32MH019113. MJM was supported by the Iowa Neuroscience Institute Summer Scholar Award. BJD was supported by NS-112573. AKH was supported by a fellowship from UGC, Govt. of India. NSN was supported by NIH National Institute of Mental Health grant R01MH116043-01A1. Tools for CHO cell research (rASIC1a-IRES2-DsRed and pcDNA3.1-rASIC2A) were given to AKB by Francois Rugiero, University College London, UK and Peter McNaughton, University of Cambridge, UK, respectively.
Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa, USA
Gail I. S. Harmata, Aubrey C. Chan, Nandakumar S. Narayanan & John A. Wemmie
Department of Psychiatry, University of Iowa, Iowa City, IA, USA
Gail I. S. Harmata, Aubrey C. Chan, Madison J. Merfeld, Rebecca J. Taugher-Hebl, Jason B. Hardie, Rong Fan, Jeffrey D. Long, Grace Z. Wang & John A. Wemmie
Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
Gail I. S. Harmata, Aubrey C. Chan, Madison J. Merfeld, Rebecca J. Taugher-Hebl, Jason B. Hardie, Rong Fan, Grace Z. Wang, Nandakumar S. Narayanan & John A. Wemmie
Department of Neurosurgery, University of Iowa, Iowa City, IA, USA
Gail I. S. Harmata, Madison J. Merfeld, Brian J. Dlouhy & John A. Wemmie
Pharmacological Sciences Predoctoral Research Training Program, Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA
Department of Veterans Affairs Medical Center, Iowa City, IA, USA
Gail I. S. Harmata, Aubrey C. Chan, Madison J. Merfeld, Rebecca J. Taugher-Hebl, Jason B. Hardie, Rong Fan, Grace Z. Wang & John A. Wemmie
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
Anjit K. Harijan & Amal K. Bera
Department of Biostatistics, University of Iowa, Iowa City, IA, USA
Department of Neurology, University of Iowa, Iowa City, IA, USA
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Roy J. Carver Chair of Psychiatry and Neuroscience, University of Iowa, Iowa City, IA, USA
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GISH conceptualized experiments, acquired data, analyzed data, interpreted data, and wrote the manuscript. ACC conceptualized experiments, acquired data, analyzed data, and interpreted data. MJM conceptualized experiments and acquired data. RJT acquired data, analyzed data, interpreted data, and wrote the manuscript. AKH acquired and analyzed data. JBH acquired and analyzed data. RF acquired data. JDL was an essential contributor to advanced data analysis. GZW acquired data. BJD conceptualized experiments, provided funding, and interpreted data. AKB conceptualized experiments. NSN conceptualized experiments and advised on data analysis. JAW conceptualized experiments, interpreted data, provided funding, and wrote the manuscript.
Correspondence to John A. Wemmie.
The authors declare no competing interests.
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Harmata, G.I.S., Chan, A.C., Merfeld, M.J. et al. Intoxicating effects of alcohol depend on acid-sensing ion channels. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01473-4
DOI: https://doi.org/10.1038/s41386-022-01473-4
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Neuropsychopharmacology (Neuropsychopharmacol.) ISSN 1740-634X (online) ISSN 0893-133X (print)