PMID- 34475522
OWN - NLM
STAT- MEDLINE
DCOM- 20220302
LR  - 20230302
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 47
IP  - 4
DP  - 2022 Mar
TI  - Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity 
      during performance of an fMRI monetary incentive delay task in individuals family 
      history positive or negative for alcohol use disorder. A pilot randomised trial.
PG  - 840-846
LID - 10.1038/s41386-021-01157-5 [doi]
AB  - Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) 
      glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been 
      implicated in animal alcohol consumption. Previously, we have described 
      differences between individuals positive (FHP) and negative (FHN) for familial 
      alcohol use disorder (AUD) in the ventral striatal (VS) activation associated 
      with monetary incentive delay task (MIDT) performance during functional magnetic 
      resonance imaging (fMRI). Here, we used AZD0530 (saracatinib), a centrally active 
      Fyn/Src inhibitor to probe the role of Fyn/Src regulation of NMDA receptors 
      (NMDAR) in VS activation differences between FHP and FHN individuals during fMRI 
      MIDT performance. We studied 21 FHN and 22 FHP individuals, all without AUD. In 
      two sessions, spaced 1 week apart, we administered 125 mg of saracatinib or 
      placebo in a double-blind manner, prior to measuring VS signal during fMRI MIDT 
      performance. MIDT comprises reward prospect, anticipation, and outcome phases. 
      During the initial (prospect of reward) task phase, there was a significant 
      group-by-condition interaction such that, relative to placebo, saracatinib 
      reduced VS BOLD signal in FHP and increased it in FHN individuals. This study 
      provides the first human evidence that elevated signaling in striatal protein 
      kinase A-dependent pathways may contribute to familial AUD risk via amplifying 
      the neural response to the prospect of reward. As Fyn kinase is responsible for 
      NMDAR upregulation, these data are consistent with previous evidence for 
      upregulated NMDAR function within reward circuitry in AUD risk. These findings 
      also suggest a possible therapeutic role for Src/Fyn kinase inhibitors in AUD 
      risk.
CI  - (c) 2021. The Author(s), under exclusive licence to American College of 
      Neuropsychopharmacology.
FAU - Patel, Krishna T
AU  - Patel KT
AUID- ORCID: 0000-0001-9210-1789
AD  - Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 
      Hartford, CT, USA. krishnapancholi@gmail.com.
FAU - Stevens, Michael C
AU  - Stevens MC
AUID- ORCID: 0000-0002-3799-5465
AD  - Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 
      Hartford, CT, USA.
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
FAU - Dunlap, Amanda
AU  - Dunlap A
AD  - Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 
      Hartford, CT, USA.
FAU - Gallagher, Alana
AU  - Gallagher A
AD  - Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 
      Hartford, CT, USA.
FAU - O'Malley, Stephanie S
AU  - O'Malley SS
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
FAU - DeMartini, Kelly
AU  - DeMartini K
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
FAU - Potenza, Marc N
AU  - Potenza MN
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
AD  - Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
AD  - Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
AD  - Connecticut Council on Problem Gambling, Wethersfield, CT, USA.
AD  - Connecticut Mental Health Center, New Haven, CT, USA.
FAU - Krystal, John H
AU  - Krystal JH
AUID- ORCID: 0000-0001-6952-1726
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
FAU - Pearlson, Godfrey D
AU  - Pearlson GD
AD  - Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 
      Hartford, CT, USA.
AD  - Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
AD  - Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
LA  - eng
GR  - P50 AA012870/AA/NIAAA NIH HHS/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210902
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Benzodioxoles)
RN  - 0 (Quinazolines)
RN  - 9KD24QGH76 (saracatinib)
SB  - IM
MH  - Alcohol Drinking
MH  - *Alcoholism/diagnostic imaging/drug therapy
MH  - Benzodioxoles
MH  - Humans
MH  - *Magnetic Resonance Imaging/methods
MH  - Motivation
MH  - Pilot Projects
MH  - Quinazolines
MH  - Reward
PMC - PMC8882177
COIS- The authors declare no competing interests.
EDAT- 2021/09/04 06:00
MHDA- 2022/03/03 06:00
PMCR- 2023/03/01
CRDT- 2021/09/03 06:41
PHST- 2021/03/12 00:00 [received]
PHST- 2021/08/09 00:00 [accepted]
PHST- 2021/08/04 00:00 [revised]
PHST- 2021/09/04 06:00 [pubmed]
PHST- 2022/03/03 06:00 [medline]
PHST- 2021/09/03 06:41 [entrez]
PHST- 2023/03/01 00:00 [pmc-release]
AID - 10.1038/s41386-021-01157-5 [pii]
AID - 1157 [pii]
AID - 10.1038/s41386-021-01157-5 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2022 Mar;47(4):840-846. doi: 10.1038/s41386-021-01157-5. 
      Epub 2021 Sep 2.