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Background: Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals., Methods: This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol clamp. Each paradigm consisted of 2 counterbalanced sessions of i.v. ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1, pancreatic polypeptide, gastric inhibitory peptide, insulin, insulin-like growth factor-1, cortisol, prolactin, and aldosterone., Results: Despite some statistical differences, findings were consistent across the 2 alcohol administration paradigms: i.v. ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1, pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session., Conclusion: These findings, gathered from a clinically relevant sample of heavy-drinking individuals with alcohol use disorder, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use., (Published by Oxford University Press on behalf of CINP 2021.)

Aims: The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys' organic anion transporter that reclaims uric acid from urine. Probenecid also inhibits pannexin1 channels that are involved in purinergic neurotransmission and inflammation, which have been implicated in alcohol's effects and motivation for alcohol. Therefore, we tested the effects of probenecid on alcohol intake in rodents., Methods: We tested the effects of probenecid on operant oral alcohol self-administration in alcohol-dependent rats during acute withdrawal as well as in nondependent rats and in the drinking-in-the-dark (DID) paradigm of binge-like drinking in mice., Results: Probenecid reduced alcohol intake in both dependent and nondependent rats and in the DID paradigm in mice without affecting water or saccharin intake, indicating that probenecid's effect was selective for alcohol and not the result of a general reduction in reward., Conclusions: These results raise the possibility that pannexin1 is a novel therapeutic target for the treatment of AUD. The clinical use of probenecid has been found to be generally safe, suggesting that it can be a candidate for drug repositioning for the treatment of AUD., (© The Author(s) 2019. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Preclinical work suggests that GET 73 (N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide), a novel metabotropic glutamate receptor subtype 5 negative allosteric modulator, may represent a novel pharmacological treatment for alcohol use disorder. Two independent experiments evaluated the effect of acutely administered GET 73 (0, 30, and 100 mg/kg, intragastrically) on alcohol-induced hypolocomotion ( n=72) and sedation/hypnosis ( n=36) in rats. In healthy male volunteers ( n=14), an open-label, randomised, crossover study was conducted to compare adverse events and pharmacokinetic parameters, in two experiments in which 300 mg GET 73 was administered, with and without alcohol, once and thrice. In rats, when administered with alcohol-vehicle, 100 mg/kg, but not 30 mg/kg, GET 73 reduced spontaneous locomotor activity. When administered with alcohol, no dose of GET 73 altered either alcohol-induced hypolocomotion or sedation/hypnosis. In humans, both single and thrice 300 mg GET 73 administration were well tolerated, in the presence and absence of alcohol, with no differences in adverse events. There were no significant differences in relative bioavailability between administering 300 mg GET 73 in the presence or absence of alcohol.

Disulfiram was the first pharmacotherapy approved to treat alcohol use disorder in the 1950s. Disulfiram alters ethanol pharmacokinetics and causes uncomfortable reactions (e.g. headache, tachycardia, nausea, flushing and hypotension) when alcohol is consumed. Subsequently, a better understanding of the neurobiological pathways involved in alcohol use disorder led to the development of other medications (e.g. naltrexone and acamprosate). These neurobiological-based medications act on alcohol use disorder-related phenotypes including craving, stress, and/or withdrawal. The original approach to treat alcohol use disorder, by altering ethanol pharmacokinetics has been much less investigated. Recent research on ethanol pharmacokinetics has shed light on the mechanisms of action underlying alcohol use disorder and how some medications that alter ethanol pharmacokinetics may be helpful in treating alcohol use disorder. This review summarizes and discusses the complex pharmacokinetics of ethanol, and proposes that altering ethanol pharmacokinetics via novel pharmacological approaches may be a viable approach to treat alcohol use disorder.

Background: Preliminary basic and human studies suggest that the α2 -adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence. The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral mechanisms of idazoxan may alter alcohol's effects., Methods: This was a preliminary double-blind, single-dose, placebo-controlled, crossover, randomized human laboratory study. Ten social drinkers were dosed, in 2 different alcohol challenge studies (ACS), with a single oral dose of idazoxan (40 mg) or placebo, followed by a fixed alcohol dose 60 minutes later. Participants returned after a 1-week washout, and they were crossed over to the opposite medication condition., Results: There were no significant differences in adverse events between idazoxan and placebo. Moreover, during the ACS paradigm, 40 mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (p < 0.01) and time to peak (p < 0.05) compared to placebo. A PK/pharmacodynamic model aligned the biobehavioral effects, demonstrating that the co-administration of 40 mg idazoxan with alcohol decreased alcohol-related stimulation (p < 0.05) and increased alcohol-related sedation (p < 0.05)., Conclusions: This study supports the safety and tolerability of 40 mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients., (Copyright © 2015 by the Research Society on Alcoholism.)

The article reports that alcohol affects several neurotransmitters and biological systems making it difficult to identify pharmacological targets for treating AUD. Topics include examines additionally, the complex constellation of AUD makes it challenging to develop effective treatments and considered precision medicine and the development of biomarkers for monitoring drug response are crucial for developing AUD pharmacotherapy.

Aims Human laboratory studies have contributed extensively in the research and development of novel medications to treat alcohol use disorder (AUD). Alcohol tolerance may represent one additional variable that can be utilized to expand the understanding of the AUD wide phenotypic profile and provide support to the medication development process. Tolerance is characterized as an individual's subjective response to alcohol and has been recognized as a predictor of AUD progression. Tolerance can be evaluated both by self-reported response (e.g. assessments) and objective measurements (e.g. motor impairment); as such, it represents an exploitable variable in the field of alcohol research. Methods This Narrative Review focuses on the use of alcohol tolerance, specifically within alcohol laboratory studies, for medication development. It seeks to identify a research gap and a research opportunity in clinical studies to evaluate biobehavioral responses captured in order to develop medications to treat AUD. Results Alcohol tolerance may provide additional information on the safety and tolerability of medications to treat AUD, in particular, when novel medications are co-administered with alcohol within the AUD population. Conclusions As such, alcohol tolerance represents an additional outcome that may be included in randomized clinical trial (RCT) protocols designed for developing AUD pharmacotherapies. [ABSTRACT FROM AUTHOR]

Aims The goal of this study was to evaluate the efficacy of topiramate up to 200 mg/day and of aripiprazole up to 15 mg/day, alone and combined, in reducing alcohol-related outcomes in a human laboratory study. Method This was a 5 week, between-subject, double-blind, placebo-controlled human laboratory study with topiramate [0 mg/day (placebo), 100 mg/day, 200 mg/day] and aripiprazole [0 mg/day (placebo), 7.5 mg/day, 15 mg/day] in 90 non-treatment seeking, heavy drinking, alcohol-dependent individuals. Main outcomes were the efficacy of 200 mg/day topiramate and 15 mg/day aripiprazole, alone and combined, in reducing drinks consumed during an alcohol self-administration procedure (human laboratory phase) and while receiving the study medications prior to the laboratory session (naturalistic drinking phase). Other outcomes in the laboratory phase included alcohol craving, and alcohol biphasic effects. Results In the human laboratory phase, topiramate 200 mg/day reduced alcohol craving [** P < 0.01] and amplified alcohol-induced stimulation [* P < 0.05], but did not reduce the number of drinks consumed. Topiramate 200 mg/day was also effective in reducing drinking days [* P < 0.05], and alcohol craving [* P < 0.05], in the naturalistic drinking phase. No significant findings were found for aripiprazole for any of the outcomes analyzed. Conclusion Participants receiving 200 mg/day topiramate reported reduced alcohol drinking and craving, and increased alcohol-related stimulation. These findings provide further support for the role of topiramate as a pharmacological treatment for AUD. ClinicalTrial.gov Identifier NCT00884884 Short Summary This study tested topiramate and aripiprazole alone and in combination. The results replicate past findings and suggest that topiramate may be an effective treatment for alcohol use disorder. The present results suggest that the combination of topiramate and aripiprazole do not warrant further evaluation. [ABSTRACT FROM AUTHOR]

Aims: The goal of this study was to evaluate the efficacy of topiramate up to 200 mg/day and of aripiprazole up to 15 mg/day, alone and combined, in reducing alcohol-related outcomes in a human laboratory study. Method: This was a 5 week, between-subject, double-blind, placebo-controlled human laboratory study with topiramate [0 mg/day (placebo), 100 mg/day, 200 mg/day] and aripiprazole [0 mg/day (placebo), 7.5 mg/day, 15 mg/day] in 90 non-treatment seeking, heavy drinking, alcohol-dependent individuals. Main outcomes were the efficacy of 200 mg/day topiramate and 15 mg/day aripiprazole, alone and combined, in reducing drinks consumed during an alcohol self-administration procedure (human laboratory phase) and while receiving the study medications prior to the laboratory session (naturalistic drinking phase). Other outcomes in the laboratory phase included alcohol craving, and alcohol biphasic effects. Results: In the human laboratory phase, topiramate 200 mg/day reduced alcohol craving [**P < 0.01] and amplified alcohol-induced stimulation [*P < 0.05], but did not reduce the number of drinks consumed. Topiramate 200 mg/day was also effective in reducing drinking days [*P < 0.05], and alcohol craving [*P < 0.05], in the naturalistic drinking phase. No significant findings were found for aripiprazole for any of the outcomes analyzed. Conclusion: Participants receiving 200 mg/day topiramate reported reduced alcohol drinking and craving, and increased alcohol-related stimulation. These findings provide further support for the role of topiramate as a pharmacological treatment for AUD. ClinicalTrial.gov Identifier: NCT00884884 Short Summary: This study tested topiramate and aripiprazole alone and in combination. The results replicate past findings and suggest that topiramate may be an effective treatment for alcohol use disorder. The present results suggest that the combination of topiramate and aripiprazole do not warrant further evaluation. [ABSTRACT FROM AUTHOR]

Corticotropin releasing factor (CRF) has been shown to induce various behavioral changes related to adaptation to stress. Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders, including substance use disorders (SUDs). CRF has been associated with stress-induced drug reinforcement. Extensive literature has identified CRF to play an important role in the molecular mechanisms that lead to an increase in susceptibility that precipitates relapse to SUDs. The CRF system has a heterogeneous role in SUDs. It enhances the acute effects of drugs of abuse and is also responsible for the potentiation of drug-induced neuroplasticity evoked during the withdrawal period. We present in this review the brain regions and circuitries where CRF is expressed and may participate in stress-induced drug abuse. Finally, we attempt to evaluate the role of modulating the CRF system as a possible therapeutic strategy for treating the dysregulation of emotional behaviors that result from the acute positive reinforcement of substances of abuse as well as the negative reinforcement produced by withdrawal. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline stress system is implicated in AUD relapse. Here, we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure to induce dependence, or withdrawn from chronic intermittent ethanol vapor exposure for 2 weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by high-performance liquid chromatography), in situ hybridization, and behavioral brain-site specific pharmacology studies were performed. We also used real-time quantitative polymerase chain reaction to assess gene expression of α 1 B , β 1 , and β 2 adrenergic receptors in human postmortem brain tissue from men diagnosed with AUD and matched control subjects. We found that α 1 receptors potentiate CeA GABAergic (gamma-aminobutyric acidergic) transmission and drive moderate alcohol intake in control rats. In dependent rats, β receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, although there are some long-lasting differences in the cellular patterns of adrenergic receptor messenger RNA expression. In addition, postmortem brain analyses reveal increased α 1 B receptor messenger RNA in the amygdala of humans with AUD. CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, supports ongoing new medication development for AUD. [ABSTRACT FROM AUTHOR]