PMID- 36793786 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240422 IS - 2296-889X (Print) IS - 2296-889X (Electronic) IS - 2296-889X (Linking) VI - 10 DP - 2023 TI - Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse. PG - 1118754 LID - 10.3389/fmolb.2023.1118754 [doi] LID - 1118754 AB - Drugs of abuse produce rearrangements at glutamatergic synapses thought to contribute to drug-reinforced behaviors. Acid-Sensing Ion Channels (ASICs) have been suggested to oppose these effects, largely due to observations in mice lacking the ASIC1A subunit. However, the ASIC2A and ASIC2B subunits are known to interact with ASIC1A, and their potential roles in drugs of abuse have not yet been investigated. Therefore, we tested the effects of disrupting ASIC2 subunits in mice exposed to drugs of abuse. We found conditioned place preference (CPP) to both cocaine and morphine were increased in Asic2 (-/-) mice, which is similar to what was observed in Asic1a (-/-) mice. Because nucleus accumbens core (NAcc) is an important site of ASIC1A action, we examined expression of ASIC2 subunits there. By western blot ASIC2A was readily detected in wild-type mice, while ASIC2B was not, suggesting ASIC2A is the predominant subunit in nucleus accumbens core. An adeno-associated virus vector (AAV) was used to drive recombinant ASIC2A expression in nucleus accumbens core of Asic2 (-/-) mice, resulting in near normal protein levels. Moreover, recombinant ASIC2A integrated with endogenous ASIC1A subunits to form functional channels in medium spiny neurons (MSNs). However, unlike ASIC1A, region-restricted restoration of ASIC2A in nucleus accumbens core was not sufficient to affect cocaine or morphine conditioned place preference, suggesting effects of ASIC2 differ from those of ASIC1A. Supporting this contrast, we found that AMPA receptor subunit composition and the ratio of AMPA receptor-mediated current to NMDA receptor-mediated current (AMPAR/NMDAR) were normal in Asic2 (-/-) mice and responded to cocaine withdrawal similarly to wild-type animals. However, disruption of ASIC2 significantly altered dendritic spine morphology, and these effects differed from those reported previously in mice lacking ASIC1A. We conclude that ASIC2 plays an important role in drug-reinforced behavior, and that its mechanisms of action may differ from ASIC1A. CI - Copyright (c) 2023 Fuller, Gupta, Fan, Taugher-Hebl, Wang, Andrys, Bera, Radley and Wemmie. FAU - Fuller, Margaret J AU - Fuller MJ AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. AD - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States. AD - Medical Scientist Training Program, University of Iowa, Iowa City, IA, United States. FAU - Gupta, Subhash C AU - Gupta SC AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. FAU - Fan, Rong AU - Fan R AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. FAU - Taugher-Hebl, Rebecca J AU - Taugher-Hebl RJ AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. FAU - Wang, Grace Z AU - Wang GZ AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. FAU - Andrys, Noah R R AU - Andrys NRR AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. FAU - Bera, Amal K AU - Bera AK AD - Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India. FAU - Radley, Jason J AU - Radley JJ AD - Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States. FAU - Wemmie, John A AU - Wemmie JA AD - Department of Psychiatry, University of Iowa, Iowa City, IA, United States. AD - Department of Veterans Affairs Medical Center, Iowa City, IA, United States. AD - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, United States. AD - Medical Scientist Training Program, University of Iowa, Iowa City, IA, United States. AD - Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, United States. AD - Department of Neurosurgery, University of Iowa, Iowa City, IA, United States. AD - Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, United States. LA - eng GR - I01 BX004440/BX/BLRD VA/United States GR - R01 DA037216/DA/NIDA NIH HHS/United States GR - R01 DA052953/DA/NIDA NIH HHS/United States PT - Journal Article DEP - 20230130 PL - Switzerland TA - Front Mol Biosci JT - Frontiers in molecular biosciences JID - 101653173 PMC - PMC9923001 OTO - NOTNLM OT - ASIC OT - ASIC2 OT - acid-sensing ion channel (ASIC) OT - cocaine OT - dendritic spines OT - morphine OT - nucleus accumbens OT - opioid COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/02/17 06:00 MHDA- 2023/02/17 06:01 PMCR- 2023/01/01 CRDT- 2023/02/16 02:21 PHST- 2022/12/07 00:00 [received] PHST- 2023/01/19 00:00 [accepted] PHST- 2023/02/16 02:21 [entrez] PHST- 2023/02/17 06:00 [pubmed] PHST- 2023/02/17 06:01 [medline] PHST- 2023/01/01 00:00 [pmc-release] AID - 1118754 [pii] AID - 10.3389/fmolb.2023.1118754 [doi] PST - epublish SO - Front Mol Biosci. 2023 Jan 30;10:1118754. doi: 10.3389/fmolb.2023.1118754. eCollection 2023.