Publications by authors named "Leandro F Vendruscolo"

74 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
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
April 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

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

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

Mechanisms of Alcohol Addiction: Bridging Human and Animal Studies.

Alcohol Alcohol 2020 Oct;55(6):603-607

Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Dr, 1882JPP, Iowa City, IA 52242-1009, USA.

Aim: The purpose of this brief narrative review is to address the complexities and benefits of extending animal alcohol addiction research to the human domain, emphasizing Allostasis and Incentive Sensitization, two models that inform many pre-clinical and clinical studies.

Methods: The work reviewed includes a range of approaches, including: a) animal and human studies that target the biology of craving and compulsive consumption; b) human investigations that utilize alcohol self-administration and alcohol challenge paradigms, in some cases across 10 years; c) questionnaires that document changes in the positive and negative reinforcing effects of alcohol with increasing severity of addiction; and d) genomic structural equation modeling based on data from animal and human studies.

Results: Several general themes emerge from specific study findings. First, positive reinforcement is characteristic of early stage addiction and sometimes diminishes with increasing severity, consistent with both Allostasis and Incentive Sensitization. Second, evidence is less consistent for the predominance of negative reinforcement in later stages of addiction, a key tenant of Allostasis. Finally, there are important individual differences in motivation to drink at a given point in time as well as person-specific change patterns across time.

Conclusions: Key constructs of addiction, like stage and reinforcement, are by necessity operationalized differently in animal and human studies. Similarly, testing the validity of addiction models requires different strategies by the two research domains. Although such differences are challenging, they are not insurmountable, and there is much to be gained in understanding and treating addiction by combining pre-clinical and clinical approaches.
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http://dx.doi.org/10.1093/alcalc/agaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576503PMC
October 2020

Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies.

Alcohol Clin Exp Res 2020 02 6;44(2):368-383. Epub 2020 Jan 6.

Department of Psychology, (KW), University of New Mexico, Albuquerque, New Mexico.

Alcohol use disorder (AUD) and chronic pain are enduring and devastating conditions that share an intersecting epidemiology and neurobiology. Chronic alcohol use itself can produce a characteristic painful neuropathy, while the regular analgesic use of alcohol in the context of nociceptive sensitization and heightened affective pain sensitivity may promote negative reinforcement mechanisms that underlie AUD maintenance and progression. The goal of this review was to provide a broad translational framework that communicates research findings spanning preclinical and clinical studies, including a review of genetic, molecular, behavioral, and social mechanisms that facilitate interactions between persistent pain and alcohol use. We also consider recent evidence that will shape future investigations into novel treatment mechanisms for pain in individuals suffering from AUD.
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http://dx.doi.org/10.1111/acer.14260DOI Listing
February 2020

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

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

Utility of fentanyl vaccines: unique challenges posed by preventing opioid overdose and treating opioid use disorder.

Neuropsychopharmacology 2019 09 24;44(10):1675-1676. Epub 2019 May 24.

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

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http://dx.doi.org/10.1038/s41386-019-0418-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785139PMC
September 2019

Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala.

PLoS Biol 2019 04 16;17(4):e2006421. Epub 2019 Apr 16.

Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.

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, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats. Intranasal oxytocin delivery fully replicated these effects. Intraperitoneal administration had minor but significant effects of reducing locomotion and intake of non-alcoholic palatable solutions, whereas intranasal oxytocin administration did not. In dependent rats, intracerebroventricular administration of oxytocin or the oxytocin receptor agonist PF-06655075, which does not cross the blood-brain barrier (i.e., it would not diffuse to the periphery), but not systemic administration of PF-06655075 (i.e., it would not reach the brain), decreased alcohol drinking. Administration of a peripherally restricted oxytocin receptor antagonist did not reverse the effect of intranasal oxytocin on alcohol drinking. Ex vivo electrophysiological recordings from CeA neurons indicated that oxytocin decreases evoked GABA transmission in nondependent but not in dependent rats, whereas oxytocin decreased the amplitude of spontaneous GABAergic responses in both groups. Oxytocin blocked the facilitatory effects of acute alcohol on GABA release in the CeA of dependent but not nondependent rats. Together, these results provide converging evidence that oxytocin specifically and selectively blocks the enhanced motivation for alcohol drinking that develops in alcohol dependence likely via a central mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol dependence. Neuroadaptations in endogenous oxytocin signaling may provide a mechanism to further our understanding of alcohol use disorder.
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http://dx.doi.org/10.1371/journal.pbio.2006421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467366PMC
April 2019

Heroin addiction engages negative emotional learning brain circuits in rats.

J Clin Invest 2019 03 26;129(6):2480-2484. Epub 2019 Mar 26.

Integrative Neuroscience Research Branch and.

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 amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.
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http://dx.doi.org/10.1172/JCI125534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546476PMC
March 2019

Male and female mice develop escalation of heroin intake and dependence following extended access.

Neuropharmacology 2019 06 14;151:189-194. Epub 2019 Mar 14.

Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA. Electronic address:

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 and female mice. Adult C57BL/6J mice were trained to nosepoke (fixed-ratio 1) to obtain intravenous heroin in six daily 1-h sessions (30-60 μg/kg/infusion). The mice were divided into short access (ShA; 1 h) and long access (LgA; 6 h) groups. Immediately after the 10th escalation session, the mice received a challenge dose of naloxone (1 mg/kg), and somatic signs of withdrawal were recorded. The mice readily acquired intravenous heroin self-administration. LgA mice escalated their drug intake in the first hour across sessions and had significantly higher scores of somatic signs of naloxone-precipitated opioid withdrawal compared with ShA mice. Female mice exhibited increases in heroin intake compared with male mice. Male and female mice exhibited similar levels of somatic signs of withdrawal. Because of the wide availability of genetically modified mouse lines, the present mouse model may be particularly useful for better understanding genetic and sex differences that underlie the transition to compulsive-like opioid taking and seeking.
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http://dx.doi.org/10.1016/j.neuropharm.2019.03.019DOI Listing
June 2019

Detecting neuroinflammation in the brain following chronic alcohol exposure in rats: A comparison between in vivo and in vitro TSPO radioligand binding.

Eur J Neurosci 2019 07 25;50(1):1831-1842. Epub 2019 Mar 25.

National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.

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) participants compared to controls. In contrast, autoradiographic findings in alcohol exposed rats reported increases in TSPO radioligand binding. To assess if these discrepancies reflected differences between in vitro and in vivo methodologies, we compared in vitro autoradiography (using [ H]PBR28 and [ H]PK11195) with in vivo PET (using [ C]PBR28) in male, Wistar rats exposed to chronic alcohol-vapor (dependent n = 10) and in rats exposed to air-vapor (nondependent n = 10). PET scans were obtained with [ C]PBR28, after which rats were euthanized and the brains were harvested for autoradiography with [ H]PBR28 and [ H]PK11195 (n = 7 dependent and n = 7 nondependent), and binding quantified in hippocampus, thalamus, and parietal cortex. Autoradiography revealed significantly higher binding in alcohol-dependent rats for both radioligands in thalamus and hippocampus (trend level for [ H]PBR28) compared to nondependent rats, and these group differences were stronger for [ H]PK11195 than [ H]PBR28. In contrast, PET measures obtained in the same rats showed no group difference in [ C]PBR28 binding. Our in vitro data are consistent with neuroinflammation associated with chronic alcohol exposure. Failure to observe similar increases in [ C]PBR28 binding in vivo suggests the possibility that a mechanism mediated by chronic alcohol exposure interferes with [ C]PBR28 binding to TSPO in vivo. These data question the sensitivity of PBR28 PET as a methodology to assess neuroinflammation in AUD.
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http://dx.doi.org/10.1111/ejn.14392DOI Listing
July 2019

Ghrelin Receptor Influence on Cocaine Reward is Not Directly Dependent on Peripheral Acyl-Ghrelin.

Sci Rep 2019 02 12;9(1):1841. Epub 2019 Feb 12.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

The peptide hormone acyl-ghrelin and its receptor, GHSR, represent intriguing therapeutic targets due to their actions in metabolic homeostasis and reward activity. However, this pleotropic activity makes it difficult to intervene in this system without inducing unwanted effects. Thus, it is desirable to identify passive and active regulatory mechanisms that allow differentiation between functional domains. Anatomical restriction by the blood brain barrier represents one major passive regulatory mechanism. However, it is likely that the ghrelin system is subject to additional passive mechanisms that promote independent regulation of orexigenic behavior and reward processing. By applying acyl-ghrelin sequestering antibodies, it was determined that peripheral sequestration of acyl-ghrelin is sufficient to blunt weight gain, but not cocaine rewarding effects. However, both weight gain and reward-associated behaviors were shown to be blocked by direct antagonism of GHSR. Overall, these data indicate that GHSR effects on reward are independent from peripheral acyl-ghrelin binding, whereas centrally-mediated alteration of energy storage requires peripheral acyl-ghrelin binding. This demonstration of variable ligand-dependence amongst functionally-distinct GHSR populations is used to generate a regulatory model for functional manipulation of specific effects when attempting to therapeutically target the ghrelin system.
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http://dx.doi.org/10.1038/s41598-019-38549-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372697PMC
February 2019

Ghrelin receptor deletion reduces binge-like alcohol drinking in rats.

J Neuroendocrinol 2019 07 16;31(7):e12663. Epub 2019 Jan 16.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, Maryland.

Ghrelin is a gastric hormone that has been implicated in the neurobiology of alcohol drinking. We have recently developed a ghrelin receptor (growth hormone secretagogue receptor; GHSR) knockout (KO) rat model, which exhibits reduced food consumption and body weight. In addition, recent preliminary work suggests that the gut-microbiome, which appears to interact with the ghrelin system, may modulate alcohol drinking. In the present study, we investigated the effects of GHSR deletion on alcohol consumption utilising GHSR KO and wild-type (WT) rats in three separate alcohol consumption paradigms: (i) operant self-administration (30-minute sessions); (ii) drinking in the dark (DID) (4-hour sessions); and (iii) intermittent access (24-hour sessions). These paradigms model varying degrees of alcohol consumption. Furthermore, we aimed to investigate the gut-microbiome composition of GHSR KO and WT rats before and after alcohol exposure. We found that the GHSR KO rats self-administered significantly less alcohol compared to WT rats in the operant paradigm, and consumed less alcohol than WT in the initial stages of the DID paradigm. No genotype differences were found in the intermittent access test. In addition, we found a significant decrease in gut-microbial diversity after alcohol exposure in both genotypes. Thus, the present results indicate that the ghrelin system may be involved in drinking patterns that result in presumably increased alcohol exposure levels. Furthermore, GHSR may constitute a potential pharmacological target for the reduction of binge-alcohol consumption. The potential functional role of the gut-microbiome in alcohol drinking, as well as interaction with the ghrelin system, is an interesting topic for further investigation.
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http://dx.doi.org/10.1111/jne.12663DOI Listing
July 2019

Influence of alcoholism and cholesterol on TSPO binding in brain: PET [C]PBR28 studies in humans and rodents.

Neuropsychopharmacology 2018 08 3;43(9):1832-1839. Epub 2018 May 3.

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

Neuroinflammation appears to contribute to neurotoxicity observed with heavy alcohol consumption. To assess whether chronic alcohol results in neuroinflammation we used PET and [C]PBR28, a ligand that binds to the 18-kDa translocator protein (TSPO), to compare participants with an alcohol use disorder (AUD: n = 19) with healthy controls (HC: n = 17), and alcohol-dependent (n = 9) with -nondependent rats (n = 10). Because TSPO is implicated in cholesterol's transport for steroidogenesis, we investigated whether plasma cholesterol levels influenced [C]PBR28 binding. [C]PBR28 binding did not differ between AUD and HC. However, when separating by TSPO genotype rs6971, we showed that medium-affinity binders AUD participants showed lower [C]PBR28 binding than HC in regions of interest (whole brain, gray and white matter, hippocampus, and thalamus), but no group differences were observed in high-affinity binders. Cholesterol levels inversely correlated with brain [C]PBR28 binding in combined groups, due to a correlation in AUD participants. In rodents, we observed no differences in brain [C]PBR28 uptake between alcohol-dependent and -nondependent rats. These findings, which are consistent with two previous [C]PBR28 PET studies, may indicate lower activation of microglia in AUD, whereas failure to observe alcohol effects in the rodent model indicate that species differences do not explain the discrepancy with prior rodent autoradiographic studies reporting increases in TSPO binding with chronic alcohol. However, reduced binding in AUD participants could also reflect competition from endogenous TSPO ligands such as cholesterol; and since the rs6971 polymorphism affects the cholesterol-binding domain of TSPO this could explain why differences were observed only in medium-affinity binders.
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http://dx.doi.org/10.1038/s41386-018-0085-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046047PMC
August 2018

Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats.

Neuropsychopharmacology 2018 11 6;43(12):2373-2382. Epub 2018 Apr 6.

Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037, USA.

The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Chronic Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake under extended access conditions, a model that mimics key features of compulsive cocaine taking. In addition, Hcrt silencing decreased motivation for both cocaine and a highly palatable food reward (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence for general measures of arousal and stress reactivity. At the molecular level, chronic Hcrt knockdown reduced the number of neurons expressing dynorphin (DYN), and to a smaller extent melanin-concentrating hormone (MCH), in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.
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http://dx.doi.org/10.1038/s41386-018-0054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180106PMC
November 2018

Unlimited sucrose consumption during adolescence generates a depressive-like phenotype in adulthood.

Neuropsychopharmacology 2018 12 27;43(13):2627-2635. Epub 2018 Feb 27.

Université Bordeaux, INCIA, UMR 5287, Bordeaux, F-33000, France.

Depression is highly prevalent worldwide, but its etiology is not fully understood. An overlooked possible contributor to the epidemic of depression is feeding styles, particularly at early age when the brain is intensely changing. We have previously reported that unlimited sucrose consumption during adolescence leads to enduring changes in brain reward function. Here, we tested the hypothesis that sucrose consumption during adolescence would lead to a 'depressive-like' phenotype. Adolescent male rats were given unlimited access to 5% sucrose in their home cages from postnatal day 30 to postnatal day 46 and their emotional behavior was subsequently examined at adulthood. Sucrose consumption during adolescence caused anhedonia, decreased motivation for saccharin, increased immobility in the forced swim test and exacerbated anxiety-like behavior. Additionally, sucrose consumption during adolescence decreased cell proliferation in the hippocampus in adulthood. Chronic treatment with imipramine (10 mg/kg) normalized behavior and restored cell proliferation in the hippocampus of adult rats with a history of sucrose consumption during adolescence. A similar sucrose consumption starting at adulthood only increases immobility in the forced swim test, suggesting that sucrose intake affects also adults' behavior but to a lesser degree. Overall, our findings reveal an unsuspected protracted effect of sucrose consumption on behavior and suggest that unlimited sucrose consumption during critical periods of brain development may play an important role in the etiology of reward-related disorders such as depression.
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http://dx.doi.org/10.1038/s41386-018-0025-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224580PMC
December 2018

Author Correction: Midbrain circuit regulation of individual alcohol drinking behaviors in mice.

Nat Commun 2018 02 8;9(1):653. Epub 2018 Feb 8.

Department of Pharmacological Sciences and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-02921-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805722PMC
February 2018

Midbrain circuit regulation of individual alcohol drinking behaviors in mice.

Nat Commun 2017 12 20;8(1):2220. Epub 2017 Dec 20.

Department of Pharmacological Sciences and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.
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http://dx.doi.org/10.1038/s41467-017-02365-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738419PMC
December 2017

Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats.

Neuropharmacology 2018 03 5;131:96-103. Epub 2017 Dec 5.

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

Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.
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http://dx.doi.org/10.1016/j.neuropharm.2017.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820113PMC
March 2018

The Role of the Ghrelin System in Drug Addiction.

Int Rev Neurobiol 2017 18;136:89-119. Epub 2017 Sep 18.

Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, United States; Center for Alcohol and Addiction Studies, Brown University, Providence, RI, United States. Electronic address:

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research.
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http://dx.doi.org/10.1016/bs.irn.2017.08.002DOI Listing
June 2018

Opiate dependence induces cell type-specific plasticity of intrinsic membrane properties in the rat juxtacapsular bed nucleus of stria terminalis (jcBNST).

Psychopharmacology (Berl) 2017 Dec 6;234(23-24):3485-3498. Epub 2017 Oct 6.

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

Rationale: Drugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique.

Results: A history of opiate dependence induced a form of cell type-specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na current (I ).

Conclusion: These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.
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http://dx.doi.org/10.1007/s00213-017-4732-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993421PMC
December 2017

Compulsive-Like Sufentanil Vapor Self-Administration in Rats.

Neuropsychopharmacology 2018 03 16;43(4):801-809. Epub 2017 Aug 16.

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

Opioid misuse is at historically high levels in the United States, with inhalation (ie, smoking and vaping) being one of the most common routes of consumption. We developed and validated a novel preclinical model of opioid self-administration by inhalation that does not require surgery and reliably produces somatic and motivational signs of dependence. Rats were trained to perform an operant response (nosepoke) to receive 10 s of vaporized sufentanil, a potent opioid, in 2 h daily sessions. Rats readily and concentration-dependently self-administered vaporized sufentanil. Rats exhibited a significant increase in responding for sufentanil when given the preferential μ-opioid receptor inverse agonist naloxone, suggesting the participation of μ-opioid receptors in the reinforcing properties of sufentanil vapor. Serum sufentanil concentrations significantly correlated with the number of sufentanil vapor deliveries. Rats that were given long access (LgA; 12 h/day) but not short access (ShA; 1 h/day) to vaporized sufentanil escalated their drug intake over time and exhibited both naloxone-precipitated somatic signs of opioid withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. After 6 months of forced drug abstinence, LgA rats returned to pre-escalation baseline levels of responding for sufentanil and mechanical sensitivity. Upon subsequent re-escalation (ie, after the return to extended access to sufentanil vapor), LgA rats again developed naloxone-precipitated somatic signs of withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. These findings demonstrate that the operant sufentanil vapor self-administration model has both face and construct validity and therefore will be useful for investigating the neurobiological basis of opioid addiction.
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http://dx.doi.org/10.1038/npp.2017.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809787PMC
March 2018

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors.

Psychoneuroendocrinology 2017 Oct 12;84:17-31. Epub 2017 Jun 12.

VA San Diego Healthcare System, San Diego, CA, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA; Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA; Department of Anesthesiology, University of California, San Diego, CA, USA.

Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre-abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naïve (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse.
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http://dx.doi.org/10.1016/j.psyneuen.2017.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557646PMC
October 2017

Dysregulation of Brain Stress Systems Mediates Compulsive Alcohol Drinking.

Curr Opin Behav Sci 2017 Feb 19;13:85-90. Epub 2016 Nov 19.

National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.

The transition from moderate to compulsive alcohol drinking is driven by increasingly dysfunctional reward and stress systems. We review behavioral and pharmacological studies of alcohol self-administration in rats that were mainly conducted within the framework of the alcohol vapor model of dependence. We discuss neurotransmitter systems that are implicated in alcohol drinking, with a focus on contrasting those neurotransmitter systems that drive behavior in the dependent . nondependent states. We hypothesize that the identification of systems that become increasingly dysfunctional in alcohol dependence will reveal possible targets for successful interventions to reduce the motivation that drives compulsive alcohol drinking. In our opinion, drugs that (1) normalize, rather than block, a hypofunctional reward system via restoration of the function of hypothalamic stress systems, and (2) desensitize extrahypothalamic stress systems have the potential to selectively and effectively curb compulsive alcohol drinking.
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http://dx.doi.org/10.1016/j.cobeha.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461929PMC
February 2017

Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents.

J Neurosci 2017 02 16;37(5):1139-1155. Epub 2016 Dec 16.

Departments of Anesthesiology and Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.

Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABA receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABA receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target.

Significance Statement: Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence-driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets.
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http://dx.doi.org/10.1523/JNEUROSCI.2002-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296793PMC
February 2017