Targeting Unmet Clinical Needs in the Treatment of Alcohol Use Disorder

Lohoff, Falk W.

doi:10.3389/fpsyt.2022.767506

Cited by 10 publications

(8 citation statements)

References 84 publications

(85 reference statements)

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“…We summarized the medications currently used and under development for AUD and MDD targeting the GABAergic system. Having considered that only three FDA drugs are available in AUD treatment while more than 20 drugs are available for MDD, the need for more potent and efficacious drugs for AUD is demanding [183]. Two recent advances in drug development are notable.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders

Ali,

Lopez

et al. 2024

Cells

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Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Most GABAergic neurons synthesize GABA from glutamate and release it in the synaptic cleft in the CNS. However, astrocytes can also synthesize and release GABA, activating GABA receptors in the neighboring neurons in physiological and pathological conditions. As the primary homeostatic glial cells in the brain, astrocytes play a crucial role in regulating GABA homeostasis and synaptic neurotransmission. Accumulating evidence demonstrates that astrocytic GABA dysregulation is implicated in psychiatric disorders, including alcohol use disorder (AUD) and major depressive disorder (MDD), the most prevalent co-occurring psychiatric disorders. Several current medications and emerging pharmacological agents targeting GABA levels are in clinical trials for treating AUD and MDD. This review offers a concise summary of the role of astrocytic GABA regulation in AUD and MDD. We also provide an overview of the current understanding and areas of debate regarding the mechanisms by which astrocytes regulate GABA in the CNS and their potential significance in the molecular basis of AUD and MDD, paving the way toward future research directions and potential therapeutic target areas within this field.

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Section: Discussionmentioning

confidence: 99%

Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders

Ali,

Lopez

et al. 2024

Cells

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“…The Seneviratne et al ( 10 ) manuscript fails to adhere to the guidelines for publication of negative data and we have found significant limitations in the data presented in that study. Currently, <10% of AUD patients are treated with pharmacological agents for their condition ( 25 ). Clinician belief that there is no efficacious or tolerated treatment for AUD mediates the low use rate of pharmacological treatment of AUD ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

A critical scientific evaluation of a purportedly negative data report – response to Seneviratne et al. 2022

Johnson,

Addolorato,

Lesch

et al. 2023

Front. Psychiatry

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A core principle in the pursuit of scientific knowledge is that science is self-correcting and that important results should be replicable. Hypotheses need to be reinforced, adjusted, or rejected when novel results are obtained. Replication of results confirms hypotheses and enhances their integration into scientific practice. In contrast, publication of substantiated and replicated negative findings (i.e., non-significant or opposite findings) can be the basis to reject erroneous hypotheses or develop alternative strategies for investigation. Replication is a problem in all research fields. The Psychology Reproductivity Project reported that only 36% of ‘highly influential’ published research in highly ranked journals were reproduced. Similar to positive data, negative data can be flawed. Errors in a negative data set can be based on methodology, statistics, conceptual defects, and flawed peer review. The peer review process has received progressive scrutiny. A large-scale review of the peer review process of manuscripts submitted to the British Medical Journal group indicated that the process could be characterized as inconsistent, inaccurate, and biased. Further analysis indicated that the peer process is easily manipulated, indicative of a failed system, is a major factor behind the lack of replication in science (acceptance of flawed manuscripts), suppresses opposing scientific evidence and views, and causes gaps in and lack of growth of science. Complicating the integrity of scientific publication is the role of Editors/Researchers. Ethical guidelines exist for major publishing houses about editorial ethics, behavior, and practice.

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“…Currently, there are only three FDA-approved treatments for AUD that all suffer from variable efficacy (Lohoff, 2022). Hence, there is an urgent need for the discovery of novel therapeutics to treat AUD.…”

Section: Introductionmentioning

confidence: 99%

Standard rodent diets differentially impact alcohol consumption and preference and gut microbiome diversity

Zaparte,

Dore,

White

et al. 2024

Preprint

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Alcohol Use Disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable rendering it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6J mice using the 24h intermittent access procedure. The three brands of chow tested were LabDiet 5001 (LD 5001), LabDiet 5053 (LD 5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo respectively). Mice fed LD5001 displayed the highest levels of alcohol consumption and preference followed by LD5053 and TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48h prior to alcohol administration. Sucrose, saccharin, and quinine preference were not altered suggesting that the diets did not alter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of “compulsive” like alcohol consumption. We profiled the gut microbiome of water and alcohol drinking mice that were maintained on different diets and found significant differences in bacterial alpha and beta diversity, which could impact gut-brain axis signaling and alcohol consumption.

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Targeting Unmet Clinical Needs in the Treatment of Alcohol Use Disorder

Cited by 10 publications

References 84 publications

Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders

Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders

A critical scientific evaluation of a purportedly negative data report – response to Seneviratne et al. 2022

Standard rodent diets differentially impact alcohol consumption and preference and gut microbiome diversity

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