Publications by authors named "George O"

149 Publications

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

Neuropharmacology 2021 Feb 26:108510. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2021.108510DOI Listing
February 2021

Primary PCI in a nonagenarian: an uncommon predicament.

BMJ Case Rep 2020 Dec 15;13(12). Epub 2020 Dec 15.

Department of Cardiology, Christian Medical College and Hospital, Vellore, India.

Myocardial infarction in a nonagenarian is a morbid cardiac illness that can lead to significant mortality unless properly dealt with management aspects. Many comorbid or family-related issues might be part of holdbacks in management of such a group of patients. Hence, myocardial infarction in a nonagenarian where intervention is better treatment option forms an uncommon combination and has many preprocedural, periprocedural and postprocedural difficulties related to multiple issues. Here, we present a case of nonagenarian who presented with extensive anterior wall MI and was successfully dealt with primary percutaneous coronary intervention despite periprocedural and intraprocedural difficulties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2020-237650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745334PMC
December 2020

A CRISPR/Cas9-based genome-editing system for yam (Dioscorea spp.).

Plant Biotechnol J 2020 Nov 22. Epub 2020 Nov 22.

International Institute of Tropical Agriculture (IITA), Nairobi, Kenya.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pbi.13515DOI Listing
November 2020

Mania presenting as a VZV encephalitis in the context of HIV.

BMJ Case Rep 2020 Sep 7;13(9). Epub 2020 Sep 7.

Department of Psychiatry, Avon and Wiltshire Mental Health Partnership NHS Trust, Bath, Bath and North East Somerset, UK.

Acute encephalitis can be life-threatening, especially in the immunocompromised population. Viruses are the main infectious agents, with varicella zoster virus (VZV) a common cause. Neuropsychiatric symptoms are well documented, but it is rare for mania to be the only symptom on presentation. Here, we report a case of hypomania in a 31-year-old white British heterosexual man who following investigation was found to be HIV positive and subsequently diagnosed with VZV encephalitis. To date, we are unaware of any similarly reported cases. It is important to raise awareness of atypical HIV presentations to improve clinical outcomes for patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2019-230512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477972PMC
September 2020

Bilateral origin of a split circumflex coronary artery.

BMJ Case Rep 2020 Sep 6;13(9). Epub 2020 Sep 6.

Cardiology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2020-237651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476456PMC
September 2020

Cardiac tumors in both twins - A case report of a rare occurrence.

Ann Pediatr Cardiol 2020 Jul-Sep;13(3):238-240. Epub 2020 Jun 11.

Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India.

Cardiac tumors in neonates and infancy are one among the many known congenital cardiac diseases. Although fetal cardiac tumors are rare, there is increased detection because of expertise in echocadiographic examination. Rhabdomyomas are the most common cardiac tumors among infants and children. Here, we describe twin neonates who had multiple cardiac tumors. This kind of presentation appears to be a very rare situation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/apc.APC_98_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437622PMC
June 2020

Advances in smoking cessation pharmacotherapy: Non-nicotinic approaches in animal models.

Neuropharmacology 2020 11 3;178:108225. Epub 2020 Aug 3.

Department of Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA; Department of Psychiatry, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA. Electronic address:

The landscape of worldwide tobacco use is changing, with a decrease in traditional smoking and an exponential rise in electronic cigarette use. No new nicotine cessation pharmacotherapies have come to market in the last 10 years. The current therapies that have been approved by the United States Food and Drug Administration for nicotine cessation include nicotine replacement therapy, varenicline, a nicotinic acetylcholine receptor partial agonist, and the atypical antidepressant bupropion. Nicotine replacement therapy and varenicline both act on nicotinic acetylcholine receptors. Bupropion inhibits the dopamine transporter, the norepinephrine transporter, and the nicotinic acetylcholine receptors to inhibit smoking behavior. Notwithstanding these treatments, rates of successful nicotine cessation in clinical trials remain low. Recent pharmacological approaches to improve nicotine cessation rates in animal models have turned their focus away from activating nicotinic acetylcholine receptors. The present review focuses on such pharmacological approaches, including nicotine vaccines, anti-nicotine antibodies, nicotine-degrading enzymes, cannabinoids, and metformin. Both immunopharmacological and enzymatic approaches rely on restricting and degrading nicotine within the periphery, thus preventing psychoactive effects of nicotine on the central nervous system. In contrast, pharmacologic inhibition of the enzymes which degrade nicotine could affect smoking behavior. Cannabinoid receptor agonists and antagonists interact with the dopamine reward pathway and show efficacy in reducing nicotine addiction-like behaviors in preclinical studies. Metformin is currently approved by the Food and Drug Administration for the treatment of diabetes. It activates specific intracellular kinases that may protect against the lower metabolism, higher oxidation, and inflammation that are associated with nicotine withdrawal. Further studies are needed to investigate non-nicotinic targets to improve the treatment of tobacco use disorder. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2020.108225DOI Listing
November 2020

Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use.

Neuropsychopharmacology 2020 10 16;45(11):1909-1919. Epub 2020 Jun 16.

Department of Neuroscience, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA, USA.

The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4β2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and β2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-0734-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608444PMC
October 2020

Depletion of the Microbiome Alters the Recruitment of Neuronal Ensembles of Oxycodone Intoxication and Withdrawal.

eNeuro 2020 May/Jun;7(3). Epub 2020 May 21.

Department of Psychiatry, University of California San Diego, La Jolla, CA 92093,

Substance use disorders have a complex etiology. Genetics, the environment, and behavior all play a role in the initiation, escalation, and relapse of drug use. Recently, opioid use disorder has become a national health crisis. One aspect of opioid addiction that has yet to be fully examined is the effects of alterations of the microbiome and gut-brain axis signaling on central nervous system activity during opioid intoxication and withdrawal. The effect of microbiome depletion on the activation of neuronal ensembles was measured by detecting Fos-positive (Fos+) neuron activation during intoxication and withdrawal using a rat model of oxycodone dependence. Daily oxycodone administration (2 mg/kg) increased pain thresholds and increased Fos+ neurons in the basolateral amygdala (BLA) during intoxication, with a decrease in pain thresholds and increase in Fos+ neurons in the periaqueductal gray (PAG), central nucleus of the amygdala (CeA), locus coeruleus (LC), paraventricular nucleus of the thalamus (PVT), agranular insular cortex (AI), bed nucleus of the stria terminalis (BNST), and lateral habenula medial parvocellular region during withdrawal. Microbiome depletion produced widespread but region- and state-specific changes in neuronal ensemble activation. Oxycodone intoxication and withdrawal also increased functional connectivity among brain regions. Microbiome depletion resulted in a decorrelation of this functional network. These data indicate that microbiome depletion by antibiotics produces widespread changes in the recruitment of neuronal ensembles that are activated by oxycodone intoxication and withdrawal, suggesting that the gut microbiome may play a role in opioid use and dependence. Future studies are needed to better understand the molecular, neurobiological, and behavioral effects of microbiome depletion on addiction-like behaviors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0312-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242819PMC
May 2020

Role of corticotropin-releasing factor in alcohol and nicotine addiction.

Brain Res 2020 08 21;1740:146850. Epub 2020 Apr 21.

Department of Psychiatry, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States. Electronic address:

The two most prevalent substance use disorders involve alcohol and nicotine, which are often co-abused. Robust preclinical and translational evidence indicates that individuals initiate drug use for the acute rewarding effects of the substance. The development of negative emotional states is key for the transition from recreational use to substance use disorders as subjects seek the substance to obtain relief from the negative emotional states of acute withdrawal and protracted abstinence. The neuropeptide corticotropin-releasing factor (CRF) is a major regulator of the brain stress system and key in the development of negative affective states. The present review examines the role of CRF in preclinical models of alcohol and nicotine abuse and explores links between CRF and anxiety-like, dysphoria-like, and other negative affective states. Finally, the present review discusses preclinical models of nicotine and alcohol use with regard to the CRF system, advances in molecular and genetic manipulations of CRF, and the importance of examining both males and females in this field of research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2020.146850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869920PMC
August 2020

Coronary artery disease management and cost implications with fractional flow reserve guided coronary intervention in Indian patients with stable ischemic coronary artery disease.

Catheter Cardiovasc Interv 2020 Apr 15. Epub 2020 Apr 15.

Department of Community Health, Christian Medical College and Hospital, Vellore, India.

Objectives: To study the safety of stent avoidance, frequency of change in management decisions, and its cost implications while using a fractional flow reserve (FFR)-guided treatment strategy for intermediate-grade coronary artery stenosis.

Background: The impact of FFR in guiding management decisions and its cost implications has not been studied after imposition of a ceiling on stent prices by the Government of India.

Methods: In 400 patients with 477 intermediate-grade coronary lesions for whom coronary intervention was planned, functional assessment using FFR was done. Incidence of the primary composite endpoint (major adverse cardiac event [MACE], cardiac death, myocardial infarction, objective evidence of ischemia, and target vessel revascularization) in the stent avoided subset was compared with the stented group at follow-up. Micro-costing analysis was done using a computed model with current stent and FFR wire prices.

Results: The overall incidence of MACE was 4.9%, 0.9% in the stent-avoided subset and 6.9% in stented group (p = 0.04, comparing the latter two) at a median follow-up of 21 months (interquartile range 12-31 months). Serious adverse events occurred only in 1% of patients receiving adenosine. The average cost saving was Indian rupees (INR) 51,847 [United States Dollar (USD) 746] per patient, resulting in total savings of INR 15,813,379 (USD 227,530). Cost savings persisted but were lower by 36% (INR 18,613/USD 268 per patient) after the ceiling of stent prices.

Conclusion: FFR-guided percutaneous coronary intervention (PCI) strategy is safe and cost-effective in countries where majority of patients self-finance their health care, resulting in stent and PCI avoidance in approximately one in three patients referred for coronary angioplasty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccd.28897DOI Listing
April 2020

Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats.

Psychopharmacology (Berl) 2020 May 29;237(5):1545-1555. Epub 2020 Feb 29.

Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive, MC 0714, La Jolla, CA, 92093-0737, USA.

Rationale: Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.

Objectives: We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.

Results: Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.

Conclusions: The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-020-05479-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269712PMC
May 2020

Chronic voluntary caffeine intake in male Wistar rats reveals individual differences in addiction-like behavior.

Pharmacol Biochem Behav 2020 04 24;191:172880. Epub 2020 Feb 24.

Department of Psychiatry, University of California San Diego, School of Medicine, MC 0714, La Jolla, CA 92093, United States of America. Electronic address:

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3 mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine preference between groups suggest that caffeine may result in compulsive-like intake in a subpopulation of subjects. Further testing is necessary to determine the factors that contribute to differences in caffeine preference and compulsive-like intake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2020.172880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269711PMC
April 2020

An arcade in the heart: Multimodality imaging.

Ann Pediatr Cardiol 2020 Jan-Mar;13(1):95-97. Epub 2019 Oct 9.

Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India.

Congenital mitral stenosis (MS) is a spectrum of anomalies that result in functional and anatomic obstruction of inflow into the left ventricle. Mitral arcade is one of the varieties of congenital MS where there is an abnormal development of chordae tendineae, resulting in stenosis, regurgitation, or both. Here, we describe the case of a mitral arcade in a child, which was diagnosed on echocardiography and confirmed with other imaging modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/apc.APC_47_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979019PMC
October 2019

Dopamine D Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats.

Front Behav Neurosci 2019 14;13:292. Epub 2020 Jan 14.

Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States.

Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%-10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D receptor antagonist VK4-116 ([R]--[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D receptor antagonism may be a viable therapeutic approach for the treatment of OUD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnbeh.2019.00292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971096PMC
January 2020

Brain-wide functional architecture remodeling by alcohol dependence and abstinence.

Proc Natl Acad Sci U S A 2020 01 14;117(4):2149-2159. Epub 2020 Jan 14.

Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA 92093;

Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1909915117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994986PMC
January 2020

Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats.

Proc Natl Acad Sci U S A 2020 01 13;117(4):2140-2148. Epub 2020 Jan 13.

Department of Psychiatry, University of California San Diego, La Jolla, CA 92093;

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1915143117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994987PMC
January 2020

Simultaneous nitriles degradation and bioflocculant production by immobilized K. oxytoca strain in a continuous flow reactor.

J Hazard Mater 2020 04 16;387:121697. Epub 2019 Nov 16.

Institute of Engineering, Architecture & Information Technology, The University of Queensland, Brisbane, QLD 4072, Australia.

High cost is one of the limiting factors in the industrial production of bioflocculant. Simultaneous preparation of bioflocculant from the contaminants in wastewater was considered as a potential approach to reduce the production cost. In this study, butyronitrile and succinonitrile were verified as sole nitrogen sources for the growth of strain K. oxytoca GS-4-08 in batch experiments. Moreover, more than 90 % of the mixed nitriles could be degraded in a continuous flow reactor, and the bioflocculant could be prepared simultaneously in the effluent. All the as-prepared bioflocculants exhibited high flocculation efficiencies of over 90 % toward Kaolin solution. FTIR and XPS results further unveiled that, the bioflocculant samples with abundance of carboxyl, amine and hydroxyl groups may play an important role on adsorption of Pd. The adsorption process could be well simulated by Freundlich model, and the K values were as high as 452.8 mg l g. The results obtained in this study not only confirm the technical feasibility for preparation of bioflocculant from various single nitrile and/or mixed nitriles, but also promise its economic feasibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2019.121697DOI Listing
April 2020

Increases in compulsivity, inflammation, and neural injury in HIV transgenic rats with escalated methamphetamine self-administration under extended-access conditions.

Brain Res 2020 01 9;1726:146502. Epub 2019 Oct 9.

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

The abuse of stimulants, such as methamphetamine (METH), is associated with treatment non-compliance, a greater risk of viral transmission, and the more rapid clinical progression of immunological and central nervous system human immunodeficiency virus (HIV) disease. The behavioral effects of METH in the setting of HIV remain largely uncharacterized. We used a state-of-the-art paradigm of the escalation of voluntary intravenous drug self-administration in HIV transgenic (Tg) and wildtype rats. The rats were first allowed to self-administer METH under short-access (ShA) conditions, which is characterized by a nondependent and more "recreational" pattern of METH use, and then allowed to self-administer METH under long-access (LgA) conditions, which leads to compulsive (dependent) METH intake. HIV Tg and wildtype rats self-administered equal amounts of METH under ShA conditions. HIV Tg rats self-administered METH under LgA conditions following a 4-week enforced abstinence period to model the intermittent pattern of stimulant abuse in humans. These HIV Tg rats developed greater motivation to self-administer METH and self-administered larger amounts of METH. Impairments in function of the medial prefrontal cortex (mPFC) contribute to compulsive drug and alcohol intake. Gene expression profiling of the mPFC in HIV Tg rats with a history of escalated METH self-administration under LgA conditions showed transcriptional evidence of increased inflammation, greater neural injury, and impaired aerobic glucose metabolism than wildtype rats that self-administered METH under LgA conditions. The detrimental effects of the interaction between neuroHIV and escalated METH intake on the mPFC are likely key factors in the greater vulnerability to excessive drug intake in the setting of HIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2019.146502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195807PMC
January 2020

Insula to ventral striatal projections mediate compulsive eating produced by intermittent access to palatable food.

Neuropsychopharmacology 2020 03 8;45(4):579-588. Epub 2019 Oct 8.

Department of Neuroscience, The Scripps Research Institute, The Scripps Research Institute, 10550N. Torrey Pines Rd., La Jolla, CA, 92037, USA.

Compulsive eating characterizes many binge-related eating disorders, yet its neurobiological basis is poorly understood. The insular cortex subserves visceral-emotional functions, including taste processing, and is implicated in drug craving and relapse. Here, via optoinhibition, we implicate projections from the anterior insular cortex to the nucleus accumbens as modulating highly compulsive-like food self-administration behaviors that result from intermittent access to a palatable, high-sucrose diet. We identified compulsive-like eating behavior in female rats through progressive ratio schedule self-administration and punishment-resistant responding, food reward tolerance and escalation of intake through 24-h energy intake and fixed-ratio operant self-administration sessions, and withdrawal-like irritability through the bottle brush test. We also identified an endocrine profile of heightened GLP-1 and PP but lower ghrelin that differentiated rats with the most compulsive-like eating behavior. Measures of compulsive eating severity also directly correlated to leptin, body weight and adiposity. Collectively, this novel model of compulsive-like eating symptoms demonstrates adaptations in insula-ventral striatal circuitry and metabolic regulatory hormones that warrant further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-019-0538-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021713PMC
March 2020

Exposure to passive nicotine vapor in male adolescent rats produces a withdrawal-like state and facilitates nicotine self-administration during adulthood.

Eur Neuropsychopharmacol 2019 11 26;29(11):1227-1234. Epub 2019 Aug 26.

Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, 92037, United States. Electronic address:

Electronic cigarette use is particularly prevalent in adolescents, but the effects of secondhand exposure to nicotine vapor in adolescents on the propensity to develop nicotine dependence and increase nicotine self-administration in adulthood are poorly known. The present study explored the effects of nicotine vapor exposure on withdrawal-like states (hyperalgesia, spontaneous withdrawal signs, and locomotor activity) in adolescent rats and the vulnerability to acquire intravenous nicotine self-administration in adulthood. Adolescent (postnatal day 38) rats were exposed to intermittent nicotine vapor (14 h/day) for 7 consecutive days in a range of doses (0, 0.4, and 7 mg/m). The rats were tested for somatic, emotional, and motivational withdrawal symptoms. When the animals reached adulthood, they were allowed to self-administer nicotine (0.03 mg/kg/0.1 ml) intravenously in operant chambers for 1 h/day for 12 consecutive days. Rats that were exposed to nicotine vapor presented moderate to severe signs of spontaneous withdrawal after the cessation of nicotine vapor. No effect on anxiety-like behavior was observed. Rats that were exposed to high levels of nicotine vapor in adolescence had lower pain thresholds and exhibited faster and higher acquisition of nicotine self-administration in adulthood. Chronic exposure to nicotine vapor in adolescent rats produced a withdrawal-like state and facilitated the acquisition of intravenous nicotine self-administration in adulthood. These results suggest that exposure of adolescents to nicotine vapor may confer higher risk of developing nicotine dependence when they become adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euroneuro.2019.08.299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899081PMC
November 2019

Systemic Administration of the Cyclin-Dependent Kinase Inhibitor (S)-CR8 Selectively Reduces Escalated Ethanol Intake in Dependent Rats.

Alcohol Clin Exp Res 2019 10 30;43(10):2079-2089. Epub 2019 Aug 30.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California.

Background: Chronic exposure to ethanol (EtOH) and other drugs of abuse can alter the expression and activity of cyclin-dependent kinase 5 (CDK5) and its cofactor p35, but the functional implication of CDK5 signaling in the regulation of EtOH-related behaviors remains unknown. In the present study, we sought to determine whether CDK5 activity plays a role in the escalation of EtOH self-administration triggered by dependence.

Methods: We tested the effect of systemically administered (S)-CR8, a nonselective CDK inhibitor, on operant responding for EtOH or saccharin, a highly palatable reinforcer, in adult male Wistar rats. Half of the rats were made EtOH-dependent via chronic intermittent EtOH inhalation (CIE). We then sought to identify a possible neuroanatomical locus for the behavioral effect of (S)-CR8 by quantifying protein levels of CDK5 and p35 in subregions of the extended amygdala and prefrontal cortex from EtOH-naïve, nondependent, and dependent rats at the expected time of EtOH self-administration. We also analyzed the phosphorylation of 4 CDK5 substrates and of the CDK substrate consensus motif.

Results: (S)-CR8 dose-dependently reduced EtOH self-administration in dependent rats. It had no effect on water or saccharin self-administration, nor in nondependent rats. The abundance of CDK5 or p35 was not altered in any of the brain regions analyzed. In the bed nucleus of the stria terminalis, CDK5 abundance was negatively correlated with intoxication levels during EtOH vapor exposure but there was no effect of dependence on the phosphorylation ratio of CDK5 substrates. In contrast, EtOH dependence increased the phosphorylation of low-molecular-weight CDK substrates in the basolateral amygdala (BLA).

Conclusions: The selective effect of (S)-CR8 on excessive EtOH intake has potential therapeutic value for the treatment of alcohol use disorders. Our data do not support the hypothesis that this effect would be mediated by the inhibition of up-regulated CDK5 activity in the extended amygdala nor prefrontal cortex. However, increased activity of CDKs other than CDK5 in the BLA may contribute to excessive EtOH consumption in alcohol dependence. Other (S)-CR8 targets may also be implicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acer.14177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779498PMC
October 2019

Adolescent Facial Acne Vulgaris and Body Mass Index: Any Relationship?

West Afr J Med 2019 May-Aug;36(2):129-132

Department of Medicine, Lagos State University Teaching Hospital, Lagos, Nigeria.

Background: Acne vulgaris is a common skin disease of adolescents. One risk factor for the development of acne is a high body mass indices. Children with high body mass index are said to be more likely to have increased Insulin-like growth factor-1, which has been implicated in acne pathogenesis. The aim of this study was to correlate body mass index with the presence and severity of facial acne vulgaris in adolescent school children.

Methods: This was a cross-sectional study in four co-educational secondary schools in Ibadan, Nigeria. One thousand and seventy nine students aged 9-20 years were physically assessed for facial acne vulgaris and their heights (m2) and weights (kg) were measured for body mass index (kg/m2) estimation. The severity of acne was assessed using the comprehensive acne severity scale. Data was analyzed using the SPSS 16.

Results: The prevalence of facial acne vulgaris was 53.2%. The age of the students ranged from 9-20 years. The mean body mass index (BMI) for the students with acne was 19.9±3.3kg/m2 and 18.3 ± 3.11 kg/m2 for students without acne, P<0.0001. The prevalence of acne was 81.7% among adolescents with a BMI >25Kg/m2, 61.1% in those with a BMI of 18.5-24.99 kg/m2 and 42.0% among adolescents with a BMI of <18.5 Kg/m2, P<0.001 but BMI was not significantly associated with severity of acne (p=0.830).

Conclusion: Adolescents with a high body mass index are more likely to have facial acne vulgaris but severity of acne is independent of body mass index.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2019

Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats.

Nat Commun 2019 03 18;10(1):1238. Epub 2019 Mar 18.

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

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-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRF pathway is mediated by inhibition of the CRF-CRF system and inhibition of BNST cell firing. These results suggest that the CRF pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09183-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423296PMC
March 2019

Genotoxic, Histopathological and Oxidative Stress Responses in Catfish, Clarias gariepinus, Exposed to Two Antifouling Paints.

J Health Pollut 2017 Dec 18;7(16):71-82. Epub 2017 Dec 18.

Environmental Toxicology and Pollution Management Laboratory, Department of Zoology, University of Lagos, Nigeria.

Background: Antifouling paints are enriched with biocides and employed in the maritime industry to protect moving and fixed surfaces from fouling activities of sea dwelling invertebrates. There is limited information on their effect on the non-target African catfish, Clarias gariepinus, a commonly consumed fish in Lagos.

Objectives: This study investigated the effects of two commonly used antifouling paints (Berger TBT-free (A/F783 (H)), reddish brown color and Silka Marine lead based paint, pale orange color) on a non-target catfish species, Clarias gariepinus.

Methods: The study involved an initial 96-hour acute toxicity assay followed by chronic toxicity evaluation (using 1/10th and 1/100th 96-hour median lethal concentration (LC) values) for 28 days to determine the ability of the paints to induce micronucleus and red blood cell abnormalities, and histopathological as well as oxidative stress effects in the catfish.Examined anti-oxidative stress enzyme activities include superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione-s-transferase (GST).

Results: Acute toxicity evaluation results indicated that the Berger paint was 16.1-times more toxic than Silka paint with 96-hour LC values of 0.71 mg/L and 11.49 mg/L, respectively. Results from the biochemical assay indicated significantly higher (P<0.05) levels of a lipid peroxidation product, malondialdehyde, in Silka-exposed catfish compared to the control. All enzymes showed significantly higher activities in Berger paint-exposed catfish compared to the control. There was evidence of micronucleated and binucleated cells in the red blood cells of fish exposed to both paints. Histopathological assessment indicated that the exposed fish gills showed evidence of abnormalities such as curved lamellae epithelial necrosis, epithelial lifting and hyperplasia. The liver samples of the catfish showed evidence of portal inflammation as well as mild to severe steatosis, while the gonads showed varying percentages of follicle degeneration.

Conclusions: The present study combined an array of biomarkers to determine the negative health impacts of two commonly used antifouling paints on non-target catfish inhabiting Lagos Lagoon. Further in situ studies are recommended to determine the current status of the lagoon fish.

Ethics Approval: Ethical approval was obtained from the Department of Zoology, University of Lagos, Post-Graduate Committee. Note that this work commenced before the establishment of the University of Lagos Ethical Committee for the use of animals and humans in scientific studies. The committee does not give retroactive approval but stands by existing approvals before its establishment. However, this study followed the World Medical Association principles on the treatment of animals used in research (https://www.wma.net/policies-post/wma-statement-on-animal-use-in-biomedical-research/), and also American Fisheries Society Guidelines for the Use of Fishes in Research (https://fisheries.org/policy-media/science-guidelines/guidelines-for-the-use-of-fishes-in-research/).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5696/2156-9614-7.16.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221448PMC
December 2017

An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse.

Sci Adv 2018 10 17;4(10):eaat4751. Epub 2018 Oct 17.

Department of Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)-induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aat4751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192681PMC
October 2018

Red colour venous flow in the suprasternal view: a red flag sign.

BMJ Case Rep 2018 Sep 30;2018. Epub 2018 Sep 30.

Department of Cardiology, Christian Medical College and Hospital Vellore, Vellore, Tamil Nadu, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2018-227257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169681PMC
September 2018

Fourteen-year-old boy with decreased appetite and pedal swelling.

Heart 2019 03 21;105(5):405-413. Epub 2018 Sep 21.

Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India.

CLINICAL INTRODUCTION: A 14-year-old boy presented with history of decreased appetite and bilateral swelling of feet for 6 months. He did not give any associated history of orthopnoea or paroxysmal nocturnal dyspnoea. He was born by a normal delivery after a non-consanguineous marriage. He had an unremarkable birth and childhood health history. There was no family history of significant cardiovascular illness or sudden death. Clinical examination showed an average built boy with elevated jugular venous pressure with prominent v wave and bilateral pitting pedal oedema. Cardiovascular examination showed normal first (S1) and second (S2) heart sounds and a short early systolic murmur over tricuspid region. Other systems examination was remarkable for soft tender hepatomegaly.ECG showed sinus rhythm with tall, peaked p waves. Chest X-ray revealed enlargement along the right cardiac border. Transthoracic echocardiographic images are shown in figure 1A (apical four-chamber view) and figure 1B (tricuspid inflow Doppler). There was no colour Doppler evidence of interatrial shunt.heartjnl;105/5/405/F1F1F1Figure 1(A) Transthoracic echocardiographic apical four-chamber view. (B) Tricuspid inflow continuous wave Doppler image. QUESTION: What is the most likely diagnosis of his condition? Endomyocardial fibrosis (EMF)Ebstein's anomalyArrhythmogenic right ventricular dysplasia (ARVD)Idiopathic dilatation of right atriumRestrictive cardiomyopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2018-313646DOI Listing
March 2019

Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood.

Sci Rep 2018 09 17;8(1):13893. Epub 2018 Sep 17.

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

Cannabis use is typically initiated during adolescence and is a significant risk factor for the development of cocaine use in adulthood. However, no preclinical studies have examined the effects of adolescent cannabinoid exposure on cocaine dependence in adulthood using the escalation model of cocaine self-administration and the assessment of negative emotional states. In the present study, we found that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) in adolescence produced irritability-like behavior and psychomotor cross-sensitization to cocaine in adolescence. In adulthood, rats were allowed to self-administer cocaine. The acquisition of cocaine self-administration was lower in rats with adolescent WIN exposure compared with controls. However, both WIN-exposed and control rats escalated their cocaine intake at the same rate, had similar responding under a progressive-ratio schedule of reinforcement, and had similar psychomotor responses to cocaine. Interestingly, the increase in irritability-like behavior that was previously observed in adolescence after WIN exposure persisted into adulthood. Whether the persisting increase in irritability-like behavior after WIN exposure has translational relevance remains to be studied. In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration. However, whether the persisting irritability-like behavior may predispose an individual to mood-related impairments in adulthood or predict such impairments warrants further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-31921-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141462PMC
September 2018

Voluntary urination control by brainstem neurons that relax the urethral sphincter.

Nat Neurosci 2018 09 13;21(9):1229-1238. Epub 2018 Aug 13.

Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.

Voluntary urination ensures that waste is eliminated when safe and socially appropriate, even without a pressing urge. Uncontrolled urination, or incontinence, is a common problem with few treatment options. Normal urine release requires a small region in the brainstem known as Barrington's nucleus (Bar), but specific neurons that relax the urethral sphincter and enable urine flow are unknown. Here we identify a small subset of Bar neurons that control the urethral sphincter in mice. These excitatory neurons express estrogen receptor 1 (Bar), project to sphincter-relaxing interneurons in the spinal cord and are active during natural urination. Optogenetic stimulation of Bar neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of urination and its dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-018-0204-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119086PMC
September 2018