Publications by authors named "George F Koob"

341 Publications

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD ( = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet ( = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.
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http://dx.doi.org/10.1126/sciadv.abf6780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034849PMC
April 2021

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction.

Sci Adv 2021 Apr 7;7(15). Epub 2021 Apr 7.

Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.

Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.
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http://dx.doi.org/10.1126/sciadv.abf0364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026136PMC
April 2021

Allostasis theory in opioid tolerance.

Pain 2021 Mar 22. Epub 2021 Mar 22.

Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, United States National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.

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http://dx.doi.org/10.1097/j.pain.0000000000002280DOI Listing
March 2021

Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.

Nat Metab 2021 03 22;3(3):337-351. Epub 2021 Mar 22.

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Alcohol is among the most widely used psychoactive substances worldwide. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to alcohol's behavioural effects and alcoholism. Here, we show that ALDH2 is expressed in astrocytes in the mouse cerebellum and that ethanol metabolism by astrocytic ALDH2 mediates behavioural effects associated with ethanol intoxication. We show that ALDH2 is expressed in astrocytes in specific brain regions and that astrocytic, but not hepatocytic, ALDH2 is required to produce ethanol-derived acetate in the mouse cerebellum. Cerebellar astrocytic ALDH2 mediates low-dose ethanol-induced elevation of GABA levels, enhancement of tonic inhibition and impairment of balance and coordination skills. Thus, astrocytic ALDH2 controls the production, cellular and behavioural effects of alcohol metabolites in a brain-region-specific manner. Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder.
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http://dx.doi.org/10.1038/s42255-021-00357-zDOI Listing
March 2021

Drug addiction co-morbidity with alcohol: Neurobiological insights.

Int Rev Neurobiol 2021 13;157:409-472. Epub 2021 Feb 13.

Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States.

Addiction is a chronic disorder that consists of a three-stage cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages involve, respectively, neuroadaptations in brain circuits involved in incentive salience and habit formation, stress surfeit and reward deficit, and executive function. Much research on addiction focuses on the neurobiology underlying single drug use. However, alcohol use disorder (AUD) can be co-morbid with substance use disorder (SUD), called dual dependence. The limited epidemiological data on dual dependence indicates that there is a large population of individuals suffering from addiction who are dependent on more than one drug and/or alcohol, yet dual dependence remains understudied in addiction research. Here, we review neurobiological data on neurotransmitter and neuropeptide systems that are known to contribute to addiction pathology and how the involvement of these systems is consistent or divergent across drug classes. In particular, we highlight the dopamine, opioid, corticotropin-releasing factor, norepinephrine, hypocretin/orexin, glucocorticoid, neuroimmune signaling, endocannabinoid, glutamate, and GABA systems. We also discuss the limited research on these systems in dual dependence. Collectively, these studies demonstrate that the use of multiple drugs can produce neuroadaptations that are distinct from single drug use. Further investigation into the neurobiology of dual dependence is necessary to develop effective treatments for addiction to multiple drugs.
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http://dx.doi.org/10.1016/bs.irn.2020.11.002DOI Listing
February 2021

Glucocorticoid receptor modulators decrease alcohol self-administration in male rats.

Neuropharmacology 2021 Feb 26;188:108510. Epub 2021 Feb 26.

Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.

Alcohol use disorder (AUD) is associated with the dysregulation of brain stress and reward systems, including glucocorticoid receptors (GRs). The mixed glucocorticoid/progesterone receptor antagonist mifepristone and selective GR antagonist CORT113176 have been shown to selectively reduce alcohol consumption in alcohol-dependent rats. Mifepristone has also been shown to decrease alcohol consumption and craving for alcohol in humans with AUD. The present study tested the effects of the GR modulators CORT118335, CORT122928, CORT108297, and CORT125134 on alcohol self-administration in nondependent (air-exposed) and alcohol-dependent (alcohol vapor-exposed) adult male rats. Different GR modulators recruit different GR-associated transcriptional cofactors. Thus, we hypothesized that these GR modulators would vary in their effects on alcohol drinking. CORT118335, CORT122928, and CORT125134 significantly reduced alcohol self-administration in both alcohol-dependent and nondependent rats. CORT108297 had no effect on alcohol self-administration in either group. The present results support the potential of GR modulators for the development of treatments for AUD. Future studies that characterize genomic and nongenomic effects of these GR modulators will elucidate potential molecular mechanisms that underlie alcohol drinking in alcohol-dependent and nondependent states.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108510DOI Listing
February 2021

Samidorphan, an opioid receptor antagonist, attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in male Wistar rats.

Pharmacol Biochem Behav 2021 May 26;204:173157. Epub 2021 Feb 26.

Alkermes, Inc., Waltham, MA 02451, USA.

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (μ), kappa- (κ), and delta- (δ) opioid receptors and functions as a μ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DA) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DA when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DA produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.
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http://dx.doi.org/10.1016/j.pbb.2021.173157DOI Listing
May 2021

Tolerance to alcohol: A critical yet understudied factor in alcohol addiction.

Pharmacol Biochem Behav 2021 May 23;204:173155. Epub 2021 Feb 23.

Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. Electronic address:

Alcohol tolerance refers to a lower effect of alcohol with repeated exposure. Although alcohol tolerance has been historically included in diagnostic manuals as one of the key criteria for a diagnosis of alcohol use disorder (AUD), understanding its neurobiological mechanisms has been neglected in preclinical studies. In this mini-review, we provide a theoretical framework for alcohol tolerance. We then briefly describe chronic tolerance, followed by a longer discussion of behavioral and neurobiological aspects that underlie rapid tolerance in rodent models. Glutamate/nitric oxide, γ-aminobutyric acid, opioids, serotonin, dopamine, adenosine, cannabinoids, norepinephrine, vasopressin, neuropeptide Y, neurosteroids, and protein kinase C all modulate rapid tolerance. Most studies have evaluated the ability of pharmacological manipulations to block the development of rapid tolerance, but only a few studies have assessed their ability to reverse already established tolerance. Notably, only a few studies analyzed sex differences. Neglected areas of study include the incorporation of a key element of tolerance that involves opponent process-like neuroadaptations. Compared with alcohol drinking models, models of rapid tolerance are relatively shorter in duration and are temporally defined, which make them suitable for combining with a wide range of classic and modern research tools, such as pharmacology, optogenetics, calcium imaging, in vivo electrophysiology, and DREADDs, for in-depth studies of tolerance. We conclude that studies of the neurobiology of alcohol tolerance should be revisited with modern conceptualizations of addiction and modern neurobiological tools. This may contribute to our understanding of AUD and uncover potential targets that can attenuate hazardous alcohol drinking.
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http://dx.doi.org/10.1016/j.pbb.2021.173155DOI Listing
May 2021

Accelerated Aging of the Amygdala in Alcohol Use Disorders: Relevance to the Dark Side of Addiction.

Cereb Cortex 2021 Feb 24. Epub 2021 Feb 24.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.

Here we assessed changes in subcortical volumes in alcohol use disorder (AUD). A simple morphometry-based classifier (MC) was developed to identify subcortical volumes that distinguished 32 healthy controls (HCs) from 33 AUD patients, who were scanned twice, during early and later withdrawal, to assess the effect of abstinence on MC-features (Discovery cohort). We validated the novel classifier in an independent Validation cohort (19 AUD patients and 20 HCs). MC-accuracy reached 80% (Discovery) and 72% (Validation). MC features included the hippocampus, amygdala, cerebellum, putamen, corpus callosum, and brain stem, which were smaller and showed stronger age-related decreases in AUD than HCs, and the ventricles and cerebrospinal fluid, which were larger in AUD and older participants. The volume of the amygdala showed a positive association with anxiety and negative urgency in AUD. Repeated imaging during the third week of detoxification revealed slightly larger subcortical volumes in AUD patients, consistent with partial recovery during abstinence. The steeper age-associated volumetric reductions in stress- and reward-related subcortical regions in AUD are consistent with accelerated aging, whereas the amygdalar associations with negative urgency and anxiety in AUD patients support its involvement in the "dark side of addiction".
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http://dx.doi.org/10.1093/cercor/bhab006DOI Listing
February 2021

A Basolateral Amygdala Microcircuit for Drug Craving: Is There a Craving Engram?

Authors:
George F Koob

Biol Psychiatry 2021 02;89(4):323-325

National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.11.008DOI Listing
February 2021

Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development.

Authors:
George F Koob

Pharmacol Rev 2021 Jan;73(1):163-201

National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland

Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.
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http://dx.doi.org/10.1124/pharmrev.120.000083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770492PMC
January 2021

Alcohol Binge Drinking: Negative and Positive Valence System Abnormalities.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jan 16;6(1):126-134. Epub 2020 Sep 16.

Division of Imaging Science and Technology, Medical School, University of Dundee, Dundee, United Kingdom. Electronic address:

Background: Each year, 3 million deaths occur owing to alcohol misuse. Translational studies are crucial to translate preclinical findings to patients. Preclinical studies have highlighted abnormalities in specific brain systems, with these forming the basis of allostasis theory. However, few studies have tested predictions in humans using neuroimaging.

Methods: We used a Research Domain Criteria approach to test allostasis theory predictions of blunted positive valence system (PVS) and abnormally increased negative valence system (NVS) responses in 57 binge alcohol drinking subjects and healthy control subjects who completed an instrumental task during functional magnetic resonance imaging.

Results: As hypothesized, binge alcohol drinkers showed abnormally increased activity in NVS-linked regions, such as the hippocampus and dorsal cingulate, and abnormally blunted activity in PVS-linked regions, such as the striatum, compared with control subjects. Higher measures of problematic alcohol use were associated with more abnormal brain activity only for binge drinkers who had been most recently drinking.

Conclusions: These results support allostasis theory predictions of abnormally increased NVS and blunted PVS responses in binge alcohol drinkers. Further similar translational neuroimaging studies are indicated, particularly focusing on the NVS.
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http://dx.doi.org/10.1016/j.bpsc.2020.09.010DOI Listing
January 2021

Addiction as a Coping Response: Hyperkatifeia, Deaths of Despair, and COVID-19.

Am J Psychiatry 2020 11;177(11):1031-1037

National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md. (all authors); National Institute on Drug Abuse, Bethesda, Md. (Koob).

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http://dx.doi.org/10.1176/appi.ajp.2020.20091375DOI Listing
November 2020

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B.

EBioMedicine 2020 Nov 21;61:103066. Epub 2020 Oct 21.

Laboratory of Psychiatric Neurogenomics, McLean Hospital, Belmont, MA 02478, United States of America. Electronic address:

Background: Slow neurotransmission including DARPP-32 signalling is implicated in substance use disorders (SUDs) by experimental systems but not yet in the human aetiology. PPP1R12B, encoding another protein in the DARPP-32 family, hasn't been studied in the brain.

Methods: Brain-regional gene activity was assessed in three different animal models of SUDs for mRNA level alterations. Genetic associations were assessed by meta-analysis of pre-existing dbGaP GWAS datasets for main effects and epistasis with known genetic risks, followed by cell type-specific pathway delineation. Parkinson's disease (PD) was included as a dopamine-related disease control for SUDs.

Findings: In animal models of SUDs, environmentally-altered PPP1R12B expression sex-dependently involves motivation-related brain regions. In humans with polysubstance abuse, meta-analysis of pre-existing datasets revealed that PPP1R12B and PPP1R1B, although expressed in dopamine vs. dopamine-recipient neurons, exerted similar interactions with known genetic risks such as ACTR1B and DRD2 in men but with ADH1B, HGFAC and DRD3 in women. These interactions reached genome-wide significances (P<10) for SUDs but not for PD (disease selectivity: P = 4.8 × 10, OR = 6.7 for PPP1R12B; P = 8.0 × 10, OR = 2.1 for PPP1R1B). CADM2 was the common risk in the molecular signalling regardless of gender and cell type.

Interpretation: Gender-dependant slow neurotransmission may convey both genetic and environmental vulnerabilities selectively to SUDs.

Funding: Grants from National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) of U.S.A. and National Natural Science Foundation of China (NSFC).
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http://dx.doi.org/10.1016/j.ebiom.2020.103066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581882PMC
November 2020

Demand for fentanyl becomes inelastic following extended access to fentanyl vapor self-administration.

Neuropharmacology 2021 01 20;182:108355. Epub 2020 Oct 20.

Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA. Electronic address:

Opioid use disorder imposes great societal harm in the United States and in countries worldwide. Animal models that accurately capture motivational changes that occur in opioid dependence are critical to studying this disorder. The present study used a model of opioid vapor self-administration combined with a behavioral economics approach to determine whether rats would be more motivated to "work" to defend their baseline intake of fentanyl (i.e., more inelastic demand) following sufficiently frequent, intense, and chronic exposure to self-administered vaporized fentanyl. Male rats were allowed to respond for deliveries of 1.5-s of vaporized 10 mg/ml fentanyl solution. Following 15 sessions of short access (ShA; 1 h) vs. long access (LgA; 12 h) to self-administration, we conducted a between-sessions demand curve procedure, and observed significantly more inelastic demand for fentanyl (Essential Value; EV), and increased maximal response output (O) in LgA compared with ShA rats. In a subsequent phase, the unit-dose was doubled to 3 s of fentanyl vaporization. After seven ShA vs. LgA sessions, we assessed demand again and found that LgA rats, contrasted to ShA rats, demonstrated significantly higher baseline intake or "hedonic setpoint" (Q), in addition to significantly increased EV and O. These results demonstrate that extended access to self-administration of a vaporized opioid causes changes in behavioral economic metrics consistent with development of an addiction-like state in rats. The combination of the vapor model with a translationally relevant behavioral economics framework opens new avenues to study dysregulated motivational processes in substance use disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747488PMC
January 2021

Converging Structural and Functional Evidence for a Rat Salience Network.

Biol Psychiatry 2020 12 2;88(11):867-878. Epub 2020 Jul 2.

Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland. Electronic address:

Background: The salience network (SN) is dysregulated in many neuropsychiatric disorders, including substance use disorder. Though the SN was initially described in humans, identification of a rodent SN would provide the ability to mechanistically interrogate this network in preclinical models of neuropsychiatric disorders.

Methods: We used modularity analysis on resting-state functional magnetic resonance imaging data of rats (n = 32) to parcellate rat insula into functional subdivisions and to identify a potential rat SN based on functional connectivity patterns from the insular subdivisions. We then used mouse tract tracing data from the Allen Brain Atlas to confirm the network's underlying structural connectivity. We next compared functional connectivity profiles of the SN across rats, marmosets (n = 10), and humans (n = 30). Finally, we assessed the rat SN's response to conditioned cues in rats (n = 21) with a history of heroin self-administration.

Results: We identified a putative rat SN, which consists of primarily the ventral anterior insula and anterior cingulate cortex, based on functional connectivity patterns from the ventral anterior insular division. Functional connectivity architecture of the rat SN is supported by the mouse neuronal tracer data. Moreover, the anatomical profile of the identified rat SN is similar to that of nonhuman primates and humans. Finally, we demonstrated that the rat SN responds to conditioned cues and increases functional connectivity to the default mode network during conditioned heroin withdrawal.

Conclusions: The neurobiological identification of a rat SN, together with a demonstration of its functional relevance, provides a novel platform with which to interrogate its functional significance in normative and neuropsychiatric disease models.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.023DOI Listing
December 2020

Reply to Cohen and Murnion.

Pain 2020 07;161(7):1683

National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.

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http://dx.doi.org/10.1097/j.pain.0000000000001891DOI Listing
July 2020

Addictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder.

Neurosci Biobehav Rev 2020 06 13;113:492-506. Epub 2020 Apr 13.

Clinical NeuroImaging Research Core, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, UK.

Alcohol misuse and addiction are major international public health issues. Addiction can be characterized as a disorder of aberrant neurocircuitry interacting with environmental, genetic and social factors. Neuroimaging in alcohol misuse can thus provide a critical window into underlying neural mechanisms, highlighting possible treatment targets and acting as clinical biomarkers for predicting risk and treatment outcomes. This neuroimaging review on alcohol misuse in humans follows the Addictions Neuroclinical Assessment (ANA) that proposes incorporating three functional neuroscience domains integral to the neurocircuitry of addiction: incentive salience and habits, negative emotional states, and executive function within the context of the addiction cycle. Here we review and integrate multiple imaging modalities focusing on underlying cognitive processes such as reward anticipation, negative emotionality, cue reactivity, impulsivity, compulsivity and executive function. We highlight limitations in the literature and propose a model forward in the use of neuroimaging as a tool to understanding underlying mechanisms and potential clinical applicability for phenotyping of heterogeneity and predicting risk and treatment outcomes.
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http://dx.doi.org/10.1016/j.neubiorev.2020.04.004DOI Listing
June 2020

The future of translational research on alcohol use disorder.

Addict Biol 2021 03 14;26(2):e12903. Epub 2020 Apr 14.

National Institute on Drug Abuse, Baltimore, Maryland, USA.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.
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http://dx.doi.org/10.1111/adb.12903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554164PMC
March 2021

Reply to Brewer: Liver-targeted ALDH2 inhibition may reduce alcohol-seeking behaviors with limited side effects.

Proc Natl Acad Sci U S A 2020 04 3;117(14):7573-7574. Epub 2020 Mar 3.

Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;

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http://dx.doi.org/10.1073/pnas.2001049117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148570PMC
April 2020

Blockade of IL-17 signaling reverses alcohol-induced liver injury and excessive alcohol drinking in mice.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Department of Surgery, and.

Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients, and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL-17 receptor A (IL-17ra-/-) or pharmacological blockade of IL-17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL-17A positively correlated with the alcohol use in excessive drinkers and was further increased in patients with ALD as compared with healthy individuals. Our data suggest that IL-17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL-17A may provide a novel strategy for treatment of alcohol-induced pathology.
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http://dx.doi.org/10.1172/jci.insight.131277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098802PMC
February 2020

An Examination of Child and Adolescent Neurodevelopment Through National Institutes of Health Studies.

Public Health Rep 2020 Mar/Apr;135(2):169-172. Epub 2020 Jan 22.

Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

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http://dx.doi.org/10.1177/0033354919900889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036611PMC
May 2020

Opioid use disorder.

Nat Rev Dis Primers 2020 01 9;6(1). Epub 2020 Jan 9.

Department of Behavioral Science, College of Medicine, University of Kentucky, Lexington, KT, USA.

Opioid use disorder (OUD) is a chronic relapsing disorder that, whilst initially driven by activation of brain reward neurocircuits, increasingly engages anti-reward neurocircuits that drive adverse emotional states and relapse. However, successful recovery is possible with appropriate treatment, although with a persisting propensity to relapse. The individual and public health burdens of OUD are immense; 26.8 million people were estimated to be living with OUD globally in 2016, with >100,000 opioid overdose deaths annually, including >47,000 in the USA in 2017. Well-conducted trials have demonstrated that long-term opioid agonist therapy with methadone and buprenorphine have great efficacy for OUD treatment and can save lives. New forms of the opioid receptor antagonist naltrexone are also being studied. Some frequently used approaches have less scientifically robust evidence but are nevertheless considered important, including community preventive strategies, harm reduction interventions to reduce adverse sequelae from ongoing use and mutual aid groups. Other commonly used approaches, such as detoxification alone, lack scientific evidence. Delivery of effective prevention and treatment responses is often complicated by coexisting comorbidities and inadequate support, as well as by conflicting public and political opinions. Science has a crucial role to play in informing public attitudes and developing fuller evidence to understand OUD and its associated harms, as well as in obtaining the evidence today that will improve the prevention and treatment interventions of tomorrow.
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http://dx.doi.org/10.1038/s41572-019-0137-5DOI Listing
January 2020

Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking.

Proc Natl Acad Sci U S A 2019 12 2;116(51):25974-25981. Epub 2019 Dec 2.

Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;

Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for detoxification the ethanol metabolite acetaldehyde, is recognized as a promising therapeutic target to treat alcohol use disorders (AUDs). Disulfiram, a potent ALDH2 inhibitor, is an approved drug for the treatment of AUD but has clinical limitations due to its side effects. This study aims to elucidate the relative contribution of different organs in acetaldehyde clearance through ALDH2 by using global- () and tissue-specific -deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior. mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specific knockout () mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed in mice. Energy expenditure and motility were dramatically dampened in mice, but moderately decreased in mice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model, mice drank negligible volumes from ethanol-containing bottles, whereas mice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specific deficiency did not affect voluntary alcohol consumption. Finally, specific liver knockdown via injection of markedly decreased alcohol preference. In conclusion, although the liver is the major organ responsible for acetaldehyde metabolism, a cumulative effect of ALDH2 from other organs likely also contributes to systemic acetaldehyde clearance. Liver-targeted ALDH2 inhibition can decrease heavy drinking without affecting moderate drinking, providing molecular basis for hepatic targeting/editing for the treatment of AUD.
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http://dx.doi.org/10.1073/pnas.1908137116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926021PMC
December 2019

PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease.

Sci Rep 2019 11 20;9(1):17167. Epub 2019 Nov 20.

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Alcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet. At the end of the alcohol exposure protocol, serum and liver samples were obtained for molecular characterization and histopathological analysis. PCSK9 inhibition with alirocumab attenuated alcohol-induced hepatic triglyceride accumulation through regulation of lipid metabolism (mRNA expression of modulators of fatty acid synthesis (FAS) and catabolism (PPARα and CPT1)), hepatocellular injury (ALT), hepatic inflammation (mRNA expression of pro-inflammatory cytokines/chemokines (TNFa, IL-1β, IL-22, IL-33, IL-17α, IL-2, MIP-2, and MCP-1), and neutrophil infiltration (myeloperoxidase staining)). Alirocumab treatment also attenuated alcohol-induced PCSK9 mRNA elevation and upregulated LDL-receptor (LDL-R) via modulation of the transcription factors (SREBP-1, SREBP-2, and E2F1) in liver. We demonstrated that chronic anti-PCSK9 treatment using the monoclonal antibody alirocumab attenuated alcohol-induced steatohepatitis in the rat model. Given the large unmet clinical need for effective and novel treatments for ALD, anti-PCSK9 treatment with the monoclonal antibody that spares liver metabolism is a viable new therapeutic possibility. Future studies are needed to elucidate the exact role of PCSK9 in ALD and alcohol use disorder (AUD) and to evaluate efficacy and safety of anti-PCSK9 treatment in clinical populations with ALD/AUD.
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http://dx.doi.org/10.1038/s41598-019-53603-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868240PMC
November 2019

A Light in the Darkness: Repetitive Transcranial Magnetic Stimulation (rTMS) to Treat the Hedonic Dysregulation of Addiction.

J Addict Med 2020 Jul/Aug;14(4):272-274

Department of Neuroscience, Imaging, and Clinical Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy (MP, MdG, GM); Department of Psychiatry, ASL Roma 5, Rome, Italy (LDR); Institute of Psychiatry and Psychology, Università Cattolica del Sacro Cuore, Rome, Italy (LDR); Department of Pharmacy, Pharmacology, and Clinical Science, University of Hertfordshire, Herts, UK (GM); National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (GFK).

: The present paper discusses the potential use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of addiction, within a conceptual framework that includes the "dark side" of addiction. New findings suggest that rTMS may rescue specific reward system dysfunction that underlies the pathophysiology of addiction by exposing widely under-recognized and untreated key clinical and psychopathological aspects of addictive disorders. Our paper sheds light on the relevance of these hidden dimensions for the development of effective treatment interventions. In particular, we argue that rTMS may have an impact on craving by reversing the allostatic load of hedonic dysregulation.
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http://dx.doi.org/10.1097/ADM.0000000000000575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214123PMC
July 2021

Probenecid Reduces Alcohol Drinking in Rodents. Is Pannexin1 a Novel Therapeutic Target for Alcohol Use Disorder?

Alcohol Alcohol 2019 Jan;54(5):497-502

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.

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.
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http://dx.doi.org/10.1093/alcalc/agz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751410PMC
January 2019

Corrigendum: Impulsivity Derived From the Dark Side: Neurocircuits That Contribute to Negative Urgency.

Front Behav Neurosci 2019;13:188. Epub 2019 Aug 27.

Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States.

[This corrects the article DOI: 10.3389/fnbeh.2019.00136.].
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http://dx.doi.org/10.3389/fnbeh.2019.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718814PMC
August 2019

Larry Stein: pioneer neuropsychopharmacology researcher, mentor, and friend.

Authors:
George F Koob

Neuropsychopharmacology 2019 12 9;44(13):2294-2295. Epub 2019 Sep 9.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41386-019-0509-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898304PMC
December 2019

Refractory dependence on opioid analgesics.

Pain 2019 12;160(12):2655-2660

National Institutes of Health, Bethesda, MD, United States.

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http://dx.doi.org/10.1097/j.pain.0000000000001680DOI Listing
December 2019