Dataset Information

Saracatinib Fails to Reduce Alcohol-Seeking and Consumption in Mice and Human Participants.

ABSTRACT: More effective treatments to reduce pathological alcohol drinking are needed. The glutamatergic system and the NMDA receptor (NMDAR), in particular, are implicated in behavioral and molecular consequences of chronic alcohol use, making the NMDAR a promising target for novel pharmacotherapeutics. Ethanol exposure upregulates Fyn, a protein tyrosine kinase that indirectly modulates NMDAR signaling by phosphorylating the NR2B subunit. The Src/Fyn kinase inhibitor saracatinib (AZD0530) reduces ethanol self-administration and enhances extinction of goal-directed ethanol-seeking in mice. However, less is known regarding how saracatinib affects habitual ethanol-seeking. Moreover, no prior studies have assessed the effects of Src/Fyn kinase inhibitors on alcohol-seeking or consumption in human participants. Here, we tested the effects of saracatinib on alcohol consumption and craving/seeking in two species, including the first trial of an Src/Fyn kinase inhibitor to reduce drinking in humans. Eighteen male C57BL/6NCrl mice underwent operant conditioning on a variable interval schedule to induce habitual responding for 10% ethanol/0.1% saccharin. Next, mice received 5 mg/kg saracatinib or vehicle 2 h or 30 min prior to contingency degradation to measure habitual responding. In the human study, 50 non-treatment seeking human participants who drank heavily and met DSM-IV criteria for alcohol abuse or dependence were randomized to receive 125 mg/day saracatinib (n = 33) or placebo (n = 17). Alcohol Drinking Paradigms (ADP) were completed in a controlled research setting: before and after 7-8 days of treatment. Each ADP involved consumption of a priming drink of alcohol (0.03 mg%) followed by ad libitum access (3 h) to 12 additional drinks (0.015 g%); the number of drinks consumed and craving (Alcohol Urge Questionnaire) were recorded. In mice, saracatinib did not affect habitual ethanol seeking or consumption at either time point. In human participants, no significant effects of saracatinib on alcohol craving or consumption were identified. These results in mice and humans suggest that Fyn kinase inhibition using saracatinib, at the doses tested here, may not reduce alcohol consumption or craving/seeking among those habitually consuming alcohol, in contrast to reports of positive effects of saracatinib in individuals that seek ethanol in a goal-directed manner. Nevertheless, future studies should confirm these negative findings using additional doses and schedules of saracatinib administration.

SUBMITTER: Thompson SL

PROVIDER: S-EPMC8438169 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundAlcohol misuse is higher in the UK armed forces (AF) than in the general population. Research demonstrates that alcohol misuse persists after an individual leaves service, and this is notably the case for those who are seeking help for a mental health difficulty. Despite this, there is no work on testing a mobile alcohol reduction intervention that is personalized to support the UK AF.ObjectiveTo address this gap, we investigated the efficacy of a 28-day brief alcohol intervention delivered via a mobile app in reducing weekly self-reported alcohol consumption among UK veterans seeking help for mental health difficulties.MethodsWe performed a 2-arm participant-blinded randomized controlled trial (RCT). We compared a mobile app that included interactive features designed to enhance participants' motivation and personalized messaging (intervention arm) with a version that provided government guidance on alcohol consumption only (control arm). Adults were eligible if they had served in the UK AF, were currently receiving or had received clinical support for mental health symptoms, and consumed 14 units (approximately 112 g of ethanol) or more of alcohol per week. Participants received the intervention or the control mobile app (1:1 ratio). The primary outcome was a change in self-reported weekly alcohol consumption between baseline and day 84 assessed using the validated Timeline Follow Back for Alcohol Consumption (TLFB) (prior 7 days), with a secondary outcome exploring self-reported change in the Alcohol Use Disorder Identification Test (AUDIT) score.ResultsBetween October 2020 and April 2021, 2708 individuals were invited to take part, of which 2531 (93.5%) did not respond, 54 (2%) were ineligible, and 123 (4.5%) responded and were randomly allocated (62, 50.4%, intervention; 61, 49.6%, control). At day 84, 41 (66.1%) participants in the intervention arm and 37 (60.7%) in the control arm completed the primary outcome assessment. Between baseline and day 84, weekly alcohol consumption reduced by -10.5 (95% CI -19.5 to -1.5) units in the control arm and -28.2 (95% CI -36.9 to -19.5) units in the intervention arm (P=.003, Cohen d=0.35). We also found a significant reduction in the AUDIT score of -3.9 (95% CI -6.2 to -1.6) in the intervention arm (Cohen d=0.48). Our primary and secondary effects did not persist over the longer term (day 168). Two adverse events were detected during the trial.ConclusionsThis study examined the efficacy of a fully automated 28-day brief alcohol intervention delivered via a mobile app in a help-seeking sample of UK veterans with hazardous alcohol consumption. We found that participants receiving Drinks:Ration reduced their alcohol consumption more than participants receiving guidance only (at day 84). In the short term, we found Drinks:Ration is efficacious in reducing alcohol consumption in help-seeking veterans.Trial registrationClinicalTrials.gov NCT04494594; https://tinyurl.com/34em6n9f.International registered report identifier (irrid)RR2-10.2196/19720.

Project description:IntroductionExcessive alcohol consumption increases the risk of many diseases and injuries, and the Global Burden of Disease 2010 study estimated that 6% of the burden of disease in Denmark is due to alcohol consumption. Alcohol consumption thus places a considerable economic burden on society.MethodsWe analysed the cost-effectiveness of six interventions aimed at preventing alcohol abuse in the adult Danish population: 30% increased taxation, increased minimum legal drinking age, advertisement bans, limited hours of retail sales, and brief and longer individual interventions. Potential health effects were evaluated as changes in incidence, prevalence and mortality of alcohol-related diseases and injuries. Net costs were calculated as the sum of intervention costs and cost offsets related to treatment of alcohol-related outcomes, based on health care costs from Danish national registers. Cost-effectiveness was evaluated by calculating incremental cost-effectiveness ratios (ICERs) for each intervention. We also created an intervention pathway to determine the optimal sequence of interventions and their combined effects.ResultsThree of the analysed interventions (advertising bans, limited hours of retail sales and taxation) were cost-saving, and the remaining three interventions were all cost-effective. Net costs varied from € -17 million per year for advertisement ban to € 8 million for longer individual intervention. Effectiveness varied from 115 disability-adjusted life years (DALY) per year for minimum legal drinking age to 2,900 DALY for advertisement ban. The total annual effect if all interventions were implemented would be 7,300 DALY, with a net cost of € -30 million.ConclusionOur results show that interventions targeting the whole population were more effective than individual-focused interventions. A ban on alcohol advertising, limited hours of retail sale and increased taxation had the highest probability of being cost-saving and should thus be first priority for implementation.

Dataset Information

Saracatinib Fails to Reduce Alcohol-Seeking and Consumption in Mice and Human Participants.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets