Medications for alcohol use disorders: An overview

Akbar, Mohammed; Egli, Mark; Cho, Young-Eun; Song, Byoung–Joon; Noronha, Antonio

doi:10.1016/j.pharmthera.2017.11.007

Cited by 75 publications

(49 citation statements)

References 269 publications

(262 reference statements)

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“…To date, only three medications are approved for alcohol dependence or prevention of relapse by the United Stated Food and Drug Administration: Disulfiram, naltrexone, and acamprosate [ 3 , 4 ]. Further, these medications are underprescribed and none are effective in a high percentage of patients [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Paternal Preconception Vapor Alcohol Exposure Paradigms on Behavioral Responses in Offspring

et al. 2020

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We and others previously reported that paternal preconception chronic ethanol exposure leads to molecular, physiological, and behavioral changes in offspring including reduced ethanol consumption and preference relative to controls. The goal of the present study was to further explore the impact of paternal ethanol exposure on a wide variety of basal and drug-induced behavioral responses in first generation offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5–6 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. E-sired male offspring showed stress hyporesponsivity in a stress-induced hyperthermia assay and E-sired female offspring had reduced binge-like ethanol consumption in a drinking in the dark assay compared to C-sired offspring. E-sired offspring also showed altered sensitivity to a sedative/hypnotic dose of the GABAergic drug midazolam, but not ketamine or ethanol, in a loss of the righting response assay. E-sired offspring did not differ from controls in marble burying, novel object location, novel object recognition, social interaction, bottle-brush, novelty suppressed feeding, prepulse inhibition, every-other-day ethanol drinking, or home cage activity assays. This study adds to a growing body of literature suggesting that like in utero alcohol exposure, paternal preconception alcohol exposure can also have effects that persist and impact behavior of offspring.

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Section: Introductionmentioning

confidence: 99%

Effects of Paternal Preconception Vapor Alcohol Exposure Paradigms on Behavioral Responses in Offspring

et al. 2020

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“…The etiology of alcohol dependence remains poorly understood, and only a few treatments are available (for reviews, see Akbar et al . #133; Heilig & Egli #73). One of the most troubling aspects of alcohol use disorder (AUD) is relapse to alcohol use that may occur even after several years of abstinence (Moos & Moos ).…”

Section: Introductionmentioning

confidence: 99%

Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein‐2 drive reinstatement of alcohol reward seeking

et al. 2018

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Alcohol use disorder is a chronic relapsing disease. Maintaining abstinence represents a major challenge for alcohol-dependent patients. Yet the molecular underpinnings of alcohol relapse remain poorly understood. In the present study, we investigated the potential role of the mammalian target of rapamycin complex 1 (mTORC1) in relapse to alcohol-seeking behavior by using the reinstatement of a previously extinguished alcohol conditioned place preference (CPP) response as a surrogate relapse paradigm. We found that mTORC1 is activated in the nucleus accumbens shell following alcohol priming-induced reinstatement of alcohol place preference. We further report that the selective mTORC1 inhibitor, rapamycin, abolishes reinstatement of alcohol place preference. Activation of mTORC1 initiates the translation of synaptic proteins, and we observed that reinstatement of alcohol CPP is associated with increased protein levels of one of mTORC1's downstream targets, collapsin response mediator protein-2 (CRMP2), in the nucleus accumbens. Importantly, the level of mTORC1 activation and CRMP2 expression positively correlate with the CPP score during reinstatement. Finally, we found that systemic administration of the CRMP2 inhibitor, lacosamide, attenuates alcohol priming-induced reinstatement of CPP. Together, our results reveal that mTORC1 and its downstream target, CRMP2, contribute to mechanisms underlying reinstatement of alcohol reward seeking. Our results could have important implications for the treatment of relapse to alcohol use and position the Food and Drug Administration approved drugs, rapamycin and lacosamide, for the treatment of alcohol use disorder.

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“…Despite the prevalence of AUD and associated binge-related alcohol abuse, individuals often receive limited or no treatment. Currently, three FDA-approved medications are available for AUD treatment: disulfiram, acamprosate and naltrexone [48]. However, these medications are often underutilized, only improve symptoms in a small fraction of treated individuals, and any improvements do not last beyond treatment [49].…”

Section: Discussionmentioning

confidence: 99%

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

et al. 2020

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Binge drinking is a dangerous pattern of behavior. We tested whether chronically manipulating nucleus accumbens (NAc) activity (via clozapine-N-oxide (CNO) and Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) could produce lasting effects on ethanol binge-like drinking in mice selectively bred to drink to intoxication. We found chronically increasing NAc activity (4 weeks, via CNO and the excitatory DREADD, hM3Dq) decreased binge-like drinking, but did not observe CNO-induced changes in drinking with the inhibitory DREADD, hM4Di. The CNO/hM3Dq-induced reduction in ethanol drinking persisted for at least one week, suggesting adaptive neuroplasticity via transcriptional and epigenetic mechanisms. Therefore, we defined this plasticity at the morphological and transcriptomic levels. We found that chronic binge drinking (6 weeks) altered neuronal morphology in the NAc, an effect that was ameliorated with CNO/hM3Dq. Moreover, we detected significant changes in expression of several plasticity-related genes with binge drinking that were ameliorated with CNO treatment (e.g., Hdac4). Lastly, we found that LMK235, an HDAC4/5 inhibitor, reduced binge-like drinking. Thus, we were able to target specific molecular pathways using pharmacology to mimic the behavioral effects of DREADDs.Brain Sci. 2020, 10, 109 2 of 22 (DID) paradigm, mice are offered an ethanol solution early into the active period of their circadian cycle and can achieve BALs >80 mg%, suggesting they drink to intoxication [1]. C57BL/6J mice are typically reported as high drinking and can achieve BALs >80mg% in the DID paradigm; however, significant inbred strain differences have been observed suggesting there exists a genetic contribution to this phenotype [2,3]. The DID assay was used to independently create two lines of mice, HDID-1 and HDID-2, that were selectively bred (from genetically heterogeneous HS/Npt progenitors) for high BALs after DID [4,5]. HDID and HS/Npt mice have been extensively characterized and HDID mice represent a unique genetic animal model of risk for drinking to intoxication [6][7][8][9][10][11][12][13][14]. FDA approved compounds for treatment of AUD, as well as several investigational compounds, have been tested for efficacy in reducing binge-like drinking using the DID paradigm in C57BL/6J and HDID mice, as well as other genotypes, with mixed results [15][16][17][18][19][20]. Together, the results of these studies suggest that testing potential therapies in more than one inbred strain may represent a more beneficial strategy for clinical translation.Koob and Volkow (2010) reviewed decades of clinical and pre-clinical studies to address the neural circuitry associated with the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation [21]. The nucleus accumbens (NAc) is identified as an important region for each of these three stages. There is also extensive evidence that altering activity in the NAc reduces alcohol drinking, craving, and relapse. To achiev...

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Medications for alcohol use disorders: An overview

Cited by 75 publications

References 269 publications

Effects of Paternal Preconception Vapor Alcohol Exposure Paradigms on Behavioral Responses in Offspring

Effects of Paternal Preconception Vapor Alcohol Exposure Paradigms on Behavioral Responses in Offspring

Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein‐2 drive reinstatement of alcohol reward seeking

Chronic Chemogenetic Stimulation of the Nucleus Accumbens Produces Lasting Reductions in Binge Drinking and Ameliorates Alcohol-Related Morphological and Transcriptional Changes

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