Prospects for pharmacotherapies to treat alcohol use disorder

Farokhnia, Mehdi; Browning, Brittney D.; Leggio, Lorenzo

doi:10.1097/yco.0000000000000519

Cited by 27 publications

(12 citation statements)

References 53 publications

(21 reference statements)

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“…In 2011 and 2014, the FDA approved two orally available PDE4-spesific inhibitors, Roflumilast and Apremilast, to treat severe COPD, psoriasis and psoriatic arthritis. Ibudilast, a dual PDE4/10 inhibitor, has shown anti-inflammatory and neuroprotective properties in humans [ 91 , 92 , 93 ]. Regarding liver diseases, the broad spectrum PDE inhibitor, Pentoxifylline, has been used in ALD and NASH patients for many years and has shown anti-inflammatory and anti-fibrotic activity [ 94 , 95 , 96 , 97 , 98 , 99 ].…”

Section: Cyclic Amp Signalingmentioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling. Hence, disturbances in cAMP homeostasis could arise at multiple levels, from changes in G protein coupled receptors and production of cAMP to the rate of degradation by phosphodiesterases. cAMP signaling plays critical roles in metabolism, inflammation and development of fibrosis in several tissues. Alcohol-associated liver disease (ALD) is a multifactorial condition ranging from a simple steatosis to steatohepatitis and fibrosis and ultimately cirrhosis, which might lead to hepatocellular cancer. To date, there is no FDA-approved therapy for ALD. Hence, identifying the targets for the treatment of ALD is an important undertaking. Several human studies have reported the changes in cAMP homeostasis in relation to alcohol use disorders. cAMP signaling has also been extensively studied in in vitro and in vivo models of ALD. This review focuses on the role of cAMP in the pathobiology of ALD with emphasis on the therapeutic potential of targeting cAMP signaling for the treatment of various stages of ALD.

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Section: Cyclic Amp Signalingmentioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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“…Topiramate is an anticonvulsant medication with multiple pharmacologic effects that inhibit neuronal activity, including enhancing gamma-aminobutyric acid (GABA) activity, suppression of voltage-sensitive Na + channels, and antagonism of glutamate transmission through effects at AMPA/kainate receptors [ 18 , 19 ]. While the mechanisms underlying the therapeutic effects of topiramate in reducing heavy drinking remain unclear, it has been hypothesized that topiramate reduces heavy drinking by inhibiting alcohol-induced dopamine release in the reward-related mesolimbic dopamine pathways by enhancing GABA neurotransmission and/or inhibiting glutamatergic neurotransmission [ 20 , 21 ]. This suppression of alcohol-induced dopamine release could decrease the reinforcing effects of alcohol.…”

Section: Introductionmentioning

confidence: 99%

Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial

Wetherill

Spilka

Jagannathan

et al. 2021

Neuropsychopharmacol.

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Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.

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“…The Food and Drug Administration (FDA) approved medications to treat AUD have shown efficacy, but their effect sizes are sub-optimal. Therefore, there is a critical need for investigating new pharmacotherapies targeting alternative pathways involved in the neurobiology of AUD ( Klein, 2016 ; Farokhnia et al, 2019a ; Witkiewitz et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

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Prospects for pharmacotherapies to treat alcohol use disorder

Cited by 27 publications

References 53 publications

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

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