PMID- 37845488
OWN - NLM
STAT- MEDLINE
DCOM- 20240320
LR  - 20240321
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 49
IP  - 5
DP  - 2024 Apr
TI  - Physiological acetic acid concentrations from ethanol metabolism stimulate 
      accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent 
      manner.
PG  - 885-892
LID - 10.1038/s41386-023-01752-8 [doi]
AB  - Recent studies have implicated the ethanol metabolite, acetic acid, as 
      neuroactive, perhaps even more so than ethanol itself. In this study, we 
      investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid 
      in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a 
      key node in the mammalian reward circuit. There was a sex-dependent difference in 
      serum acetate production, quantified via ion chromatography only at the lowest 
      dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh 
      medium spiny neurons (MSN) in brain slices demonstrated that physiological 
      concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in 
      both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, 
      robustly attenuated the acetic acid-induced increase in excitability. Acetic 
      acid-induced NMDAR-dependent inward currents were greater in females compared to 
      males and were not estrous cycle dependent. These findings suggest a novel 
      NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may 
      influence neurophysiological effects in a key reward circuit in the brain from 
      ethanol consumption. Furthermore, these findings also highlight a specific 
      sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may 
      underlie their more rapid advancement to alcohol use disorder and increased risk 
      of alcohol related neurodegeneration compared to males.
CI  - (c) 2023. The Author(s), under exclusive licence to American College of 
      Neuropsychopharmacology.
FAU - Chapp, Andrew D
AU  - Chapp AD
AD  - Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
AD  - Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN, 
      55445, USA.
FAU - Nwakama, Chinonso A
AU  - Nwakama CA
AUID- ORCID: 0000-0002-5167-7949
AD  - Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA.
AD  - Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN, 
      55445, USA.
AD  - Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New 
      York, NY, 10029, USA.
FAU - Collins, Andrea R
AU  - Collins AR
AD  - Department of Psychiatry, University of California San Francisco Fresno, Fresno, 
      CA, 93701, USA.
FAU - Mermelstein, Paul G
AU  - Mermelstein PG
AD  - Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA. 
      pmerm@umn.edu.
AD  - Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN, 
      55445, USA. pmerm@umn.edu.
AD  - Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, 
      MN, 55455, USA. pmerm@umn.edu.
FAU - Thomas, Mark J
AU  - Thomas MJ
AUID- ORCID: 0000-0001-5721-5350
AD  - Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA. 
      tmhomas@umn.edu.
AD  - Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN, 
      55445, USA. tmhomas@umn.edu.
AD  - Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, 
      MN, 55455, USA. tmhomas@umn.edu.
LA  - eng
GR  - T32 DA007234/DA/NIDA NIH HHS/United States
PT  - Journal Article
DEP - 20231016
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3K9958V90M (Ethanol)
SB  - IM
UOF - bioRxiv. 2023 May 05;:. PMID: 37205358
MH  - Animals
MH  - Female
MH  - Male
MH  - *Nucleus Accumbens
MH  - *Neurons/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Medium Spiny Neurons
MH  - Ethanol/pharmacology
MH  - Mammals/metabolism
PMC - PMC10948831
COIS- The authors declare no competing interests.
EDAT- 2023/10/17 00:42
MHDA- 2024/03/20 06:45
PMCR- 2025/04/01
CRDT- 2023/10/16 23:39
PHST- 2023/05/08 00:00 [received]
PHST- 2023/10/02 00:00 [accepted]
PHST- 2023/09/05 00:00 [revised]
PHST- 2025/04/01 00:00 [pmc-release]
PHST- 2024/03/20 06:45 [medline]
PHST- 2023/10/17 00:42 [pubmed]
PHST- 2023/10/16 23:39 [entrez]
AID - 10.1038/s41386-023-01752-8 [pii]
AID - 1752 [pii]
AID - 10.1038/s41386-023-01752-8 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2024 Apr;49(5):885-892. doi: 10.1038/s41386-023-01752-8. 
      Epub 2023 Oct 16.