George F. Koob's research while affiliated with National Institute on Drug Abuse and other places

Publications (1,000)

Article
Alcohol use is increasing among adults 65 and older and the size of this population is expanding rapidly. Aging is associated with systemic inflammation, sleep disturbances, cancers, cognitive decline and increased risk of injury and death from falls and other accidents. Alcohol misuse exacerbates and accelerates these age-related changes. Older dr...
Article
Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral...
Article
Full-text available
The prevalence of sleep disruptions is higher among people with alcohol use disorder (AUD), particularly during alcohol withdrawal, compared to non-AUD individuals. Although women generally have a higher risk of developing sleep disorders, few studies have investigated sex differences in sleep disruptions following chronic alcohol exposure. The pre...
Article
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The global crisis of opioid overdose fatalities has led to an urgent search to discover the neurobiological mechanisms of opioid use disorder (OUD). A driving force for OUD is the dysphoric and emotionally painful state (hyperkatifeia) that is produced during acute and protracted opioid withdrawal. Here, we explored a mechanistic role for extrahypo...
Article
The objective of this article is to provide an operational definition of recovery from alcohol use disorder (AUD) to facilitate the consistency of research on recovery and stimulate further research. The construct of recovery has been difficult to operationalize in the alcohol treatment and recovery literature. Several formal definitions of recover...
Chapter
Drug addiction has been defined as a chronically relapsing disorder that is characterized by a compulsion to seek and take a drug or stimulus, the loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug or stimulus is prevented, a component of which is anhedonia. The present review explores a heur...
Article
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Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal...
Article
Understanding the interface between opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) is challenging. By use of a dimensional framework, such as research domain criteria, convergent and targetable neurobiological processes in OUD–PTSD comorbidity can be identified. We hypothesise that, in OUD–PTSD, circuitry that is implicated in...
Article
A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities in pancreatic pain. The event was held on July 21, 2021, and structured into 4 sessions: (1) pathophysiology; (2) biomarkers, mediators, and pharmacology of pain; (3) pain assessment; and (4) pain treatment ch...
Article
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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. W...
Article
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Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hype...
Article
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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...
Article
Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human labora...
Article
Full-text available
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...
Article
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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 (Disco...
Chapter
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...
Article
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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....
Article
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 provid...
Article
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...
Article
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)...
Article
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 determ...
Article
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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 o...
Article
Background Three million deaths occur each year due 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 neuroimag...
Article
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Cocaine-induced vasoconstriction reduces blood flow, which can jeopardize neuronal function and in the prefrontal cortex (PFC) it may contribute to compulsive cocaine intake. Here, we used integrated optical imaging in a rat self-administration and a mouse noncontingent model, to investigate whether changes in the cerebrovascular system in the PFC...
Preprint
Full-text available
Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, i.e., the effects of alcohol on the ghrelin system, remains to be fully established. To characterize the downstream effects of alcohol on the ghrelin system, we examined the following: (1) plasma ghre...
Article
Full-text available
Background The salience network (SN) is dysregulated in many neuropsychiatric disorders, including substance use disorder. 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 res...
Article
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...
Article
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 an...
Article
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 an...
Chapter
Excessive alcohol consumption leads a spectrum of liver disorders from simple steatosis (fatty liver) to severe forms of liver injury including steatohepatitis, cirrhosis, and hepatocellular carcinoma. Many proinflammatory mediators, metabolic pathways, transcriptional factors, and epigenetic factors have been identified to contribute to the develo...
Article
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. Th...
Chapter
Psychostimulant drugs, such as cocaine and amphetamines, of the indirect sympathomimetic class have a long history as tonics and other preparations to allay fatigue and sustain performance. These drugs also have a long history of abuse and dependence. Abuse potential varies with the availability of the drug both environmentally and physiologically,...
Article
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 eluc...
Article
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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. Alir...
Article
: 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 wide...
Article
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Negative urgency is a unique dimension of impulsivity that involves acting rashly when in extreme distress and impairments in inhibitory control. It has been hypothesized to derive from stress that is related to negative emotional states that are experienced during the withdrawal/negative affect stage of the addiction cycle. Classically, a transiti...
Article
The development of alcohol use disorder (AUD) involves binge drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negativ...
Article
Opioids are powerful drugs that usurp and overpower the reward function of endogenous opioids and engage dramatic tolerance and withdrawal via molecular and neurocircuitry neuroadaptations within the same reward system. However, they also engage the brain systems for stress and pain (somatic and emotional) while producing hyperalgesia and hyperkati...
Data
Responding/reinforcement on the water lever during pharmacological testing. Water responding remained low relative to alcohol responding/reinforcement in all pharmacological tests. (A) Oxytocin decreased water responding/reinforcement following intraperitoneal administration regardless of group (F4, 72 = 4.32, p < 0.01). Post hoc analyses indicated...
Data
Baseline operant responding/reinforcement (FR1) for 10% alcohol (w/v) and water prior to pharmacological testing of intraperitoneal and intranasal oxytocin. (A) Last 8 sessions of operant alcohol self-administration training (FR1) prior to intraperitoneal testing. A 2 × 8 (Group × Session) R.M. ANOVA confirmed a significant effect of Group (F1,18 =...
Article
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Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin’s effects on dependence-induced alcohol drinking, enha...
Data
Effect of OTA on sIPSCs. The oxytocin receptor antagonist OTA did not affect sIPSC frequency, amplitude, or kinetics in CeA neurons from dependent animals. CeA, central nucleus of the amygdala; OTA, desGly-NH2-d(CH2)5[D-Tyr2,Thr4]OVT; sIPSC, spontaneous inhibitory postsynaptic current. (TIF)
Data
Effect of alcohol and TMA on eIPSPs. Alcohol (44 mM) increased evoked GABA responses in neurons from nondependent and dependent rats, an effect unaffected by the vasopressin 1A receptor antagonist TMA. eIPSP, evoked inhibitory postsynaptic potential; TMA, (d(CH2)5,Tyr(Me)2,Arg8)-Vasopressin. (TIF)
Data
Effect of oxytocin on spike frequency. Spike frequency at 2 injected currents under baseline conditions for neurons from nondependent (200 pA: 1.55 ± 0.46 spikes, 400 pA: 4.18 ± 0.57 spikes) and alcohol-dependent (200 pA: 2.47 ± 0.55 spikes, 400 pA: 4.73 ± 0.91 spikes) rats. Oxytocin (500 nM) did not alter spike frequency at either current level fo...
Data
Effect of TMA on sIPSCs. Baseline GABAA-mediated sIPSC frequency, amplitude, and kinetic measurements (rise and decay time) are unaffected by vasopressin 1A receptor antagonist (TMA) application in CeA neurons from nondependent and alcohol dependent rats. CeA, central nucleus of the amygdala; sIPSC, spontaneous inhibitory postsynaptic current; TMA,...
Data
I/O baseline eIPSP amplitude relationship for nondependent and alcohol-dependent animals. eIPSP I/O curves generated by 5 equivalent normalized stimulus intensities between nondependent (3.7 ± 0.3, 7.0 ± 0.6, 9.7 ± 0.7, 12.2 ± 0.8, and 14.7 ± 0.9 mV) and dependent (3.7 ± 0.3, 6.8 ± 0.5, 9.9 ± 0.7, 12.8 ± 0.8, and 14.9 ± 0.9 mV) animals. eIPSP, evok...
Data
This file contains supplemental methods and results. (DOCX)
Data
Effect of OTA on eIPSPs. The oxytocin receptor antagonist OTA did not affect eIPSP amplitude but blocked oxytocin induced decreases in amplitude and restored ethanol induced increases in amplitude in CeA neurons from nondependent animals. CeA, central nucleus of the amygdala; eIPSP, evoked inhibitory postsynaptic potential; OTA, desGly-NH2-d(CH2)5[...
Data
This file contains the raw data presented in figures in the main manuscript (Figs 1–5) and supplemental figures (S1–S8 Figs). (XLSX)
Article
Neurons in the periaqueductal gray (PAG) integrate negative emotions with the autonomic, neuroendocrine, and immune systems to facilitate responses to threat. Modern functional track tracing in animals and optogenetic and chemogenetic techniques show that the PAG is a rich substrate for the integration of active and passive responses to threat. In...
Article
Full-text available
Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of am...
Article
Full-text available
The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-rele...
Article
Opioid use disorder is a serious public health issue in the United States. Animal models of opioid dependence are fundamental for studying the etiology of addictive behaviors. We tested the hypothesis that extended access to heroin self-administration leads to increases in heroin intake and produces somatic signs of opioid dependence in both male a...
Article
Full-text available
Excessive alcohol consumption is associated with neuroinflammation, which likely contributes to alcohol‐related pathology. However, positron emission tomography (PET) studies using radioligands for the 18‐kDa translocator protein (TSPO), which is considered a biomarker of neuroinflammation, reported decreased binding in alcohol use disorder (AUD) p...