PMID- 31251994
OWN - NLM
STAT- MEDLINE
DCOM- 20200721
LR  - 20201002
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 157
DP  - 2019 Oct
TI  - A novel NMDA receptor-based intervention to suppress compulsion-like alcohol 
      drinking.
PG  - 107681
LID - S0028-3908(19)30239-4 [pii]
LID - 10.1016/j.neuropharm.2019.107681 [doi]
AB  - Compulsive drives for alcohol, where intake persists despite adverse 
      consequences, are substantial obstacles to treating Alcohol Use Disorder (AUD). 
      However, there are limited treatment options and thus considerable interest in 
      identifying new, potent and safe pharmacotherapies. We found that non-canonical 
      N-methyl-d-aspartate receptors (NMDARs), active at hyperpolarized potentials, 
      drive compulsion-like alcohol drinking in rats without affecting regular, 
      alcohol-only intake. Congruent human studies suggest that NMDAR inhibition 
      reduces alcohol drinking in treatment-seekers but not non-treatment-seekers and 
      suppresses craving. These cross-species studies of consumption under conflict 
      indicate that inhibiting non-canonical NMDARs could be of clinical value for AUD. 
      d-serine activates NMDARs overall, but actually inhibits non-canonical NMDARs. 
      Also, d-serine has been widely tested in humans as a moderate NMDAR modulator, 
      but some nephrotoxicity concerns remain, and thus any strategy that reduces 
      d-serine exposure could be of broad utility. Here, co-administration of sodium 
      benzoate (NaBenz), which reduces d-serine breakdown, allowed subthreshold 
      d-serine levels to suppress compulsion-like alcohol drinking without altering 
      normal alcohol-only consumption, providing a novel intervention for AUD and 
      underscoring the importance of non-canonical NMDARs for compulsion-like intake. 
      Low NaBenz doses alone had no average effect on intake. NaBenz/d-serine reduced 
      compulsion-like intake in nearly all animals, while higher d-serine alone 
      decreased compulsion-like intake with less of an effect in lower-drinking 
      subjects. Thus, combining subthreshold NaBenz and d-serine suppressed 
      compulsion-like intake, helping both to alleviate some d-serine concerns, and, 
      importantly, to reduce consequence-resistant consumption across nearly all 
      individuals. Therefore, NaBenz/d-serine likely represents an FDA-approved and 
      immediately-accessible pharmacotherapy to help counteract compulsion-like drives 
      and treat AUD.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Wegner, Scott Andrew
AU  - Wegner SA
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA.
FAU - Hu, Bing
AU  - Hu B
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA.
FAU - De Oliveira Sergio, Thatiane
AU  - De Oliveira Sergio T
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA.
FAU - Darevsky, David
AU  - Darevsky D
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA.
FAU - Kwok, Claudina Choi-Yan
AU  - Kwok CC
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA.
FAU - Lei, Kelly
AU  - Lei K
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA.
FAU - Hopf, Frederic Woodward
AU  - Hopf FW
AD  - Alcohol and Addiction Research Group, Department of Neurology, University of 
      California at San Francisco, San Francisco, CA, USA; Wheeler Center for the Study 
      of Addiction, University of California at San Francisco, USA. Electronic address: 
      Frederic.Hopf@ucsf.edu.
LA  - eng
GR  - R01 AA024109/AA/NIAAA NIH HHS/United States
GR  - R21 AA021445/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190625
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 452VLY9402 (Serine)
RN  - OJ245FE5EU (Sodium Benzoate)
SB  - IM
MH  - Alcohol Drinking/*prevention & control
MH  - Animals
MH  - Compulsive Behavior/*prevention & control
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Excitatory Amino Acid Antagonists/*pharmacology
MH  - Isomerism
MH  - Male
MH  - Rats
MH  - Serine/*pharmacology
MH  - Sodium Benzoate/*pharmacology
PMC - PMC6677620
MID - NIHMS1534319
OTO - NOTNLM
OT  - Addiction
OT  - Alcohol
OT  - Compulsive
OT  - NMDA receptor
OT  - Pathological
OT  - Treatment
COIS- Declarations of Interest None.
EDAT- 2019/06/30 06:00
MHDA- 2020/07/22 06:00
PMCR- 2020/10/01
CRDT- 2019/06/29 06:00
PHST- 2018/11/16 00:00 [received]
PHST- 2019/06/19 00:00 [revised]
PHST- 2019/06/21 00:00 [accepted]
PHST- 2019/06/30 06:00 [pubmed]
PHST- 2020/07/22 06:00 [medline]
PHST- 2019/06/29 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - S0028-3908(19)30239-4 [pii]
AID - 10.1016/j.neuropharm.2019.107681 [doi]
PST - ppublish
SO  - Neuropharmacology. 2019 Oct;157:107681. doi: 10.1016/j.neuropharm.2019.107681. 
      Epub 2019 Jun 25.