Abstract
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.
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This study was funded by 2P50 AA012870 to JK. Study drug and placebo were provided by Astra-Zeneca. Dr. Potenza has consulted for and advised Game Day Data, the Addiction Policy Forum, AXA, Idorsia, and Opiant Therapeutics; has received research support from the Connecticut Council on Problem Gambling, Mohegan Sun Casino, and the National Center for Responsible Gaming (now the International Center for Responsible Gambling); has participated in surveys, mailings, or telephone consultations related to addictions, impulse-control disorders or other health topics; has consulted for law offices and the federal public defender’s office in issues related to impulse-control and addictive disorders; has provided clinical care in the Connecticut Department of Mental Health and Addiction Services Problem Gambling Services Program; has performed grant reviews for the National Institutes of Health and other agencies; has edited journals and journal sections; has given academic lectures in grand rounds, CME events and other clinical/scientific venues; and has generated books or chapters for publishers of mental health texts. All other authors report no biomedical financial interests or potential conflicts of interest.
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KTP, GDP, MCS, SOM MNP & JHK all contributed to manuscript authorship. KTP performed statistical analyses. AD and AG were responsible for subject recruitment and data collection. KDM was responsible for administrative aspects of the study. All authors reviewed & commented on the final manuscript.
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Patel, K.T., Stevens, M.C., Dunlap, A. et al. 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. Neuropsychopharmacol. 47, 840–846 (2022). https://doi.org/10.1038/s41386-021-01157-5
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DOI: https://doi.org/10.1038/s41386-021-01157-5
