Journal articles on the topic 'Preclinical models of addiction'
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Singer, Bryan F. "Diverse Characteristics of Addiction Necessitate Multiple Preclinical Models." Biological Psychiatry 86, no. 11 (December 2019): e43-e45. http://dx.doi.org/10.1016/j.biopsych.2019.09.024.
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Yahyavi-Firouz-Abadi, Noushin, and Ronald E. See. "Anti-relapse medications: Preclinical models for drug addiction treatment." Pharmacology & Therapeutics 124, no. 2 (November 2009): 235–47. http://dx.doi.org/10.1016/j.pharmthera.2009.06.014.
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Banks, Matthew L., and S. Stevens Negus. "Insights from Preclinical Choice Models on Treating Drug Addiction." Trends in Pharmacological Sciences 38, no. 2 (February 2017): 181–94. http://dx.doi.org/10.1016/j.tips.2016.11.002.
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Schulteis, Gery, Lisa H. Gold, and George F. Koob. "Preclinical Behavioral Models for Addressing Unmet Needs in Opiate Addiction." Seminars in Neuroscience 9, no. 3-4 (1997): 94–109. http://dx.doi.org/10.1006/smns.1997.0110.
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Peters, Jamie, and David E. Olson. "Engineering Safer Psychedelics for Treating Addiction." Neuroscience Insights 16 (January 2021): 263310552110338. http://dx.doi.org/10.1177/26331055211033847.
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Addiction is best described as a disorder of maladaptive neuroplasticity involving the simultaneous strengthening of reward circuitry that drives compulsive drug seeking and weakening of circuits involved in executive control over harmful behaviors. Psychedelics have shown great promise for treating addiction, with many people attributing their therapeutic effects to insights gained while under the influence of the drug. However, psychedelics are also potent psychoplastogens—molecules capable of rapidly re-wiring the adult brain. The advent of non-hallucinogenic psychoplastogens with anti-addictive properties raises the intriguing possibility that hallucinations might not be necessary for all therapeutic effects of psychedelic-based medicines, so long as the underlying pathological neural circuitry can be remedied. One of these non-hallucinogenic psychoplastogens, tabernanthalog (TBG), appears to have long-lasting therapeutic effects in preclinical models relevant to alcohol and opioid addiction. Here, we discuss the implications of these results for the development of addiction treatments, as well as the next steps for advancing TBG and related non-hallucinogenic psychoplastogens as addiction therapeutics.
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ROTHMAN, RICHARD B., GREGORY I. ELMER, TONI S. SHIPPENBERG, WILLIAM REA, and MICHAEL H. BAUMANN. "Phentermine and Fenfluramine: Preclinical Studies in Animal Models of Cocaine Addiction." Annals of the New York Academy of Sciences 844, no. 1 (May 1998): 59–74. http://dx.doi.org/10.1111/j.1749-6632.1998.tb08222.x.
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Menne, Victoria, and Rose Chesworth. "Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms." Neuroanatomy and Behaviour 2 (January 16, 2020): e10. http://dx.doi.org/10.35430/nab.2020.e10.
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Schizophrenia is a severe psychiatric disorder which is worsened substantially by substance abuse/addiction. Substance abuse affects nearly 50% of individuals with schizophrenia, extends across several drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants) and worsens overall functioning of patients. Prominent theories explaining schizophrenia and addiction comorbidity include the primary addiction hypothesis (i.e. schizophrenia susceptibility primes drug reward circuits, increasing drug addiction risk following drug exposure), the two-hit hypothesis (i.e. drug abuse and other genetic and/or environmental risk factors contribute to schizophrenia development) and the self-medication hypothesis (i.e. drug use alleviates schizophrenia symptoms). Animal models can be used to evaluate the utility and validity of these theories. Since this literature was last reviewed by Ng and colleagues in 2013 [Neurosci Biobehav Rev, 37(5)], significant advances have been made to our understanding of schizophrenia and substance abuse comorbidity. Here we review advances in the field since 2013, focussing on two key questions: 1) Does schizophrenia susceptibility increase susceptibility to drug addiction (assessing the primary addiction hypothesis), and 2) Do abused drugs exacerbate or ameliorate schizophrenia symptoms (assessing the two-hit hypothesis and the self-medication hypothesis). We addressed these questions using data from several schizophrenia preclinical models (e.g. genetic, lesion, neurodevelopmental, pharmacological) across drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants). We conclude that addiction-like behaviour is present in several preclinical schizophrenia models, and drugs of abuse can exacerbate but also ameliorate schizophrenia-relevant behaviours. These behavioural changes are associated with altered receptor system function (e.g. dopaminergic, glutamatergic, GABAergic) critically implicated in schizophrenia and addiction pathology.
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McLemon, Erin, and Rose Chesworth. "Cannabinoid treatment of opiate addiction." Neuroanatomy and Behaviour 3 (June 12, 2021): e14. http://dx.doi.org/10.35430/nab.2021.e14.
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Opioid abuse is a growing global problem. Current therapies for opioid abuse target withdrawal symptoms and have several adverse side effects. There are no treatments to address opioid-induced neural adaptations associated with abuse and addiction. Preclinical research demonstrates interactions between the endogenous opioid and cannabinoid systems, suggesting that cannabinoids may be used to treat opioid addiction and dependence. The aim of this review is to assess how cannabinoids affect behavioural and molecular measures of opioid dependence and addiction-like behaviour in animal models. It appears that cannabidiol and cannabinoid receptor 1 (CB1R) antagonists have potential for treating drug-craving and drug-seeking behaviour, based on evidence from preclinical animal models. Ligands which inhibit the action of cannabinoid degradation enzymes also show promise in reducing opioid withdrawal symptoms and opioid self-administration in rodents. Agonists of CB1R could be useful for treating symptoms of opioid withdrawal; however, the clinical utility of these drugs is limited by side effects, the potential for cannabinoid addiction and an increase in opiate tolerance induced by cannabinoid consumption. The mechanisms by which cannabinoids reduce opioid addiction-relevant behaviours include modulation of cannabinoid, serotonin, and dopamine receptors, as well as signalling cascades involving ERK-CREB-BDNF and peroxisome proliferator-activated receptor-α. Identifying the receptors involved and their mechanism of action remains a critical area of future research.
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Duncan, Jhodie R., and Andrew J. Lawrence. "The role of metabotropic glutamate receptors in addiction: Evidence from preclinical models." Pharmacology Biochemistry and Behavior 100, no. 4 (February 2012): 811–24. http://dx.doi.org/10.1016/j.pbb.2011.03.015.
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Belin-Rauscent, Aude, Maxime Fouyssac, Antonello Bonci, and David Belin. "How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction." Biological Psychiatry 79, no. 1 (January 2016): 39–46. http://dx.doi.org/10.1016/j.biopsych.2015.01.004.
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Kawa, Alex B., Florence Allain, Terry E. Robinson, and Anne-Noël Samaha. "The transition to cocaine addiction: the importance of pharmacokinetics for preclinical models." Psychopharmacology 236, no. 4 (February 28, 2019): 1145–57. http://dx.doi.org/10.1007/s00213-019-5164-0.
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Sustkova-Fiserova, Magdalena, Chrysostomos Charalambous, Anna Khryakova, Alina Certilina, Marek Lapka, and Romana Šlamberová. "The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions." International Journal of Molecular Sciences 23, no. 2 (January 11, 2022): 761. http://dx.doi.org/10.3390/ijms23020761.
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Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin’s/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin’s/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.
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Augier, Eric. "Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder." Alcohol and Alcoholism 56, no. 2 (February 9, 2021): 139–48. http://dx.doi.org/10.1093/alcalc/agab003.
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Abstract Aims The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABAB receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness. Methods This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABAB PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABAB PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABAB PAMs to attenuate multiple alcohol-related behaviors will be discussed. Results Positive allosteric modulators (PAMs) of the GABAB receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABAB agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABAB PAMs for addiction treatment. Conclusions Preclinical studies indicate that GABAB PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABAB agonism. This predicts that GABAB PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.
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Tzschentke, Thomas. "Behavioral pharmacology of buprenorphine, with a focus on preclinical models of reward and addiction." Psychopharmacology 161, no. 1 (April 1, 2002): 1–16. http://dx.doi.org/10.1007/s00213-002-1003-8.
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Korpi, Esa R. "Addiction as an adaptation process in the brain, a view from neurobiology." International Journal of Alcohol and Drug Research 4, no. 1 (June 22, 2015): 91–94. http://dx.doi.org/10.7895/ijadr.v4i1.194.
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Korpi, E. (2015). Addiction as an adaptation process in the brain, a view from neurobiology. The International Journal Of Alcohol And Drug Research, 4(1), 91-94. doi:http://dx.doi.org/10.7895/ijadr.v4i1.194Research on the brain mechanisms of dependence on alcohol and drugs of abuse has rapidly advanced during the last two decades. We know the main processes, especially how the drugs are acting on their targets on brain cells, but this basic knowledge has not been well translated to better therapies. Not surprisingly, neurobiological addiction research is tackling the same fundamental questions as all neuropsychiatric research. For example, what are the roles of individual neuronal populations in different phases of addiction (development, maintenance, craving and compulsion, abstinence and relapse)? For preclinical research, novel neurogenetic methods now show great promise to answer at least some of the questions, but more innovative work is required to build models and find mechanisms for social and environmental interactions in addiction and to translate the inventions to clinical therapies. Addiction as a disease concept still gives a proper framework for this line of important research.
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Davis, Caroline. "From Passive Overeating to “Food Addiction”: A Spectrum of Compulsion and Severity." ISRN Obesity 2013 (May 15, 2013): 1–20. http://dx.doi.org/10.1155/2013/435027.
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A psychobiological dimension of eating behaviour is proposed, which is anchored at the low end by energy intake that is relatively well matched to energy output and is reflected by a stable body mass index (BMI) in the healthy range. Further along the continuum are increasing degrees of overeating (and BMI) characterized by more severe and more compulsive ingestive behaviours. In light of the many similarities between chronic binge eating and drug abuse, several authorities have adopted the perspective that an apparent dependence on highly palatable food—accompanied by emotional and social distress—can be best conceptualized as an addiction disorder. Therefore, this review also considers the overlapping symptoms and characteristics of binge eating disorder (BED) and models of food addiction, both in preclinical animal studies and in human research. It also presents this work in the context of the modern and “toxic” food environment and therein the ubiquitous triggers for over-consumption. We complete the review by providing evidence that what we have come to call “food addiction” may simply be a more acute and pathologically dense form of BED.
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Hakimian, Joshua K., Tien S. Dong, Jorge A. Barahona, Venu Lagishetty, Suchi Tiwari, Darien Azani, Matthew Barrera, et al. "Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome." Nutrients 11, no. 8 (August 14, 2019): 1900. http://dx.doi.org/10.3390/nu11081900.
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Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.
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Grabowska, Karolina, Wojciech Ziemichód, and Grażyna Biała. "Recent Studies on the Development of Nicotine Abuse and Behavioral Changes Induced by Chronic Stress Depending on Gender." Brain Sciences 13, no. 1 (January 10, 2023): 121. http://dx.doi.org/10.3390/brainsci13010121.
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Nowadays, stressful situations are an unavoidable element of everyday life. Stressors activate a number of complex mental and physiological reactions in the organism, thus affecting the state of health of an individual. Stress is the main risk factor in the development of mental disorders, such as depression and other disorders developing as a result of addiction. Studies indicate that women are twice as likely as men to develop anxiety, depression and therefore addiction, e.g., to nicotine. Even though the data presented is indicative of significant differences between the sexes in the prevalence of these disorders, the majority of preclinical animal models for investigating stress-induced disorders use predominantly male subjects. However, the recent data indicates that this type of studies has also been launched in female rodents. Therefore, conducting research on both sexes allows for a more accurate understanding and assessment of the impact of stress on stress-induced behavioral, peripheral and molecular changes in the body and brain. In this manuscript we have gathered the data from 41 years (from 1981–2022) on the influence of stress on the development of depression and nicotine addiction in both sexes.
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Luijten, Maartje, Matt Field, and Ingmar H. A. Franken. "Pharmacological interventions to modulate attentional bias in addiction." CNS Spectrums 19, no. 3 (August 1, 2013): 239–46. http://dx.doi.org/10.1017/s1092852913000485.
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Attentional bias in substance-dependent patients is the tendency to automatically direct attention to substance-related cues in the environment. Preclinical models suggest that attentional bias emerges as a consequence of dopaminergic activity evoked by substance-related cues. The aim of the current review is to describe pharmacological mechanisms underlying attentional bias in humans and to critically review empirical studies that aimed to modulate attentional bias in substance-dependent patients by using pharmacological agents. The findings of the reviewed studies suggest that attentional bias and related brain activation may be modulated by dopamine. All of the reviewed studies investigated acute effects of pharmacological agents, while measurements of chronic pharmacological treatments on attentional bias and clinically relevant measures such as relapse are yet lacking. Therefore, the current findings should be interpreted as a proof of principle concerning the role of dopamine in attentional bias. At the moment, there is too little evidence for clinical applications. While the literature search was not limited to dopamine, there is a lack of studies investigating the role of non-dopaminergic neurotransmitter systems in substance-related attentional bias. A focus on neurotransmitter systems such as acetylcholine and noradrenaline could provide new insights regarding the pharmacology of substance-related attentional bias.
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Van Hedger, Kathryne, Meredith J. Kushner, Royce Lee, and Harriet de Wit. "Oxytocin Reduces Cigarette Consumption in Daily Smokers." Nicotine & Tobacco Research 21, no. 6 (April 26, 2018): 799–804. http://dx.doi.org/10.1093/ntr/nty080.
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Abstract Introduction Despite widespread knowledge of the dangers of cigarette consumption, smoking continues to be a public health concern. One compound that has shown potential for treatment in preclinical models is the neuropeptide oxytocin (OT). The purpose of the present study was to examine the effects of intranasal oxytocin on cigarette craving, behavioral economic demand for cigarettes, and cigarette consumption, in regular smokers after 18 hours of abstinence. Method Otherwise healthy daily smokers (n = 35) completed two sessions where they received OT (40 IU intranasal) or placebo (PBO) and completed measures of craving and cigarette demand, and they were given six opportunities to smoke partial cigarettes in exchange for money. Results On average participants smoked few cigarettes after receiving OT than after receiving PBO, and they reported less desire for additional cigarettes during the smoking period. OT did not affect cigarette demand or standardized measures of cigarette craving. Conclusions This study suggests that OT decreases some indices of smoking desire and consumption, providing modest support for the idea that OT might be effective for reducing cigarette smoking. Implications This study provides new evidence that oxytocin might have clinical value in the treatment of addictive disorders, in this case tobacco addiction. The study adds to a growing literature suggesting that this neuropeptide, which is mainly known for its role in social bonding and attachment, may also affect mood and motivational states relevant to addiction.
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Kor, Ariel, Amir Djalovski, Marc N. Potenza, Orna Zagoory-Sharon, and Ruth Feldman. "Alterations in oxytocin and vasopressin in men with problematic pornography use: The role of empathy." Journal of Behavioral Addictions 11, no. 1 (March 28, 2022): 116–27. http://dx.doi.org/10.1556/2006.2021.00089.
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Abstract Background Addictive behaviors share clinical, genetic, neurobiological and phenomenological parallels with substance addictions. Despite the prevalence of compulsive sexual behaviors, particularly problematic pornography use (PPU), how neuroendocrine systems relate to PPU is not well understood. Preclinical studies demonstrate alterations in oxytocin and arginine vasopressin (AVP) function in animal models of addiction, but no human study has tested their involvement in PPU. Method Participants included 122 males; 69 reported PPU, and 53 were demographically-matched participants without PPU. Plasma oxytocin and AVP levels and oxytocin-to-AVP balance were measured at baseline. Salivary oxytocin was assessed at baseline and in response to four videos depicting neutral/positive social encounters. Participants reported on empathy and psychiatric symptoms. Results Baseline plasma AVP levels were elevated in men with PPU, and the ratio of oxytocin-to-vasopressin suggested AVP dominance. Men with PPU reacted with greater oxytocin increases to presentation of neutral/positive social stimuli. Decreased empathic tendencies were found in men with PPU, and this reduced empathy mediated links between oxytocin and pornography-related hypersexuality. Structural equation modeling revealed three independent paths to pornography-related hypersexuality; two direct paths via increased AVP and higher psychiatric symptoms and one indirect path from oxytocin to pornography-related hypersexuality mediated by diminished empathy. Conclusions Findings are among the first to implicate neuropeptides sustaining mammalian attachment in the pathophysiology of pornography-related hypersexuality and describe a neurobiological mechanism by which oxytocin-AVP systems and psychiatric symptomatology may operate to reduce empathy and lead to pornography-related hypersexuality.
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Sánchez-Salvador, Lucía, Ángeles Prados-Pardo, Elena Martín-González, Manuela Olmedo-Córdoba, Santiago Mora, and Margarita Moreno. "The Role of Social Stress in the Development of Inhibitory Control Deficit: A Systematic Review in Preclinical Models." International Journal of Environmental Research and Public Health 18, no. 9 (May 6, 2021): 4953. http://dx.doi.org/10.3390/ijerph18094953.
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Inhibitory control deficit and impulsivity and compulsivity behaviours are present in different psychopathological disorders such as addiction, obsessive-compulsive disorders and schizophrenia, among others. Social relationships in humans and animals are governed by social organization rules, which modulate inhibitory control and coping strategies against stress. Social stress is associated with compulsive alcohol and drug use, pointing towards a determining factor in an increased vulnerability to inhibitory control deficit. The goal of the present review is to assess the implication of social stress and dominance on the vulnerability to develop impulsive and/or compulsive spectrum disorders, with the aid of the information provided by animal models. A systematic search strategy was carried out on the PubMed and Web of Science databases, and the most relevant information was structured in the text and tables. A total of 34 studies were recruited in the qualitative synthesis. The results show the role of social stress and dominance in increased drug and alcohol use, aggressive and impulsive behaviour. Moreover, the revised studies support the role of Dopaminergic (DA) activity and the alterations in the dopaminergic D1/D2 receptors as key factors in the development of inhibitory control deficit by social stress.
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Tateishi, Kensuke, Nobuyoshi Sasaki, Masahito Kawazu, Yohei Miyake, Taishi Nakamura, Yukie Yoshii, Yuko Matsushita, et al. "TB-02 NF-KB CANONICAL PATHWAY ACTIVATION DRIVES GLYCOLYSIS AND TUMOR PROGRESSION IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA." Neuro-Oncology Advances 1, Supplement_2 (December 2019): ii10. http://dx.doi.org/10.1093/noajnl/vdz039.045.
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Abstract Recent genomic analyses have identified highly recurrent genetic alterations in PCNSL. However, due to the lack of clinically representative PCNSL preclinical models, the pathogenic mechanisms of these alterations remains largely unknown. Here, we established the largest panel of 12 clinically relevant PCNSL patient-derived orthotopic xenografts retained the histopathologic phenotype, lymphoma expression subtype, copy number alterations and 90% of the non-synonymous mutations of primary tumors, with 100% concordance of MYD88 and CD79B mutations, which are highly recurrent in PCNSL. Patient tumor regression with high-dose methotrexate correlated with in vitro sensitivity to methotrexate in corresponding PCNSL models. By knocking down canonical NF-kB pathway genes, we found that successful orthotopic xenograft formation was dependent on NF-kB canonical pathway activation induced by MYD88 mutation or overexpression of EBV-related LMP1. Metabolically, PCNSL xenografts phenocopied the high 18F-fluorodeoxyglucose uptake observed in patients and demonstrated glycolytic dependence, revealing new potential therapeutic strategies in PCNSL. Collectively, we found NF-kB canonical pathway activation as a crucial driver of PCNSL xenograft progression and found that NF-kB canonical pathway induced an addiction to glycolysis, revealing a novel potential therapeutic strategy. Our PCNSL xenograft panel represents a valuable and reproducible preclinical tool that has the potential to help decipher how genetic and/or epigenetic alterations contributes to lymphomagenesis and tumor maintenance and enhance the development of novel therapeutic strategies in PCNSL.
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Piquet-Pessôa, Marcelo, Samuel R. Chamberlain, Rico S. C. Lee, Gabriela M. Ferreira, Marcelo S. Cruz, Ana P. Ribeiro, Gabriela B. de Menezes, Lucy Albertella, Murat Yücel, and Leonardo F. Fontenelle. "A study on the correlates of habit-, reward-, and fear-related motivations in alcohol use disorder." CNS Spectrums 24, no. 6 (March 27, 2019): 597–604. http://dx.doi.org/10.1017/s1092852918001554.
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ObjectiveWe assessed self-reported drives for alcohol use and their impact on clinical features of alcohol use disorder (AUD) patients. Our prediction was that, in contrast to “affectively” (reward or fear) driven drinking, “habitual” drinking would be associated with worse clinical features in relation to alcohol use and higher occurrence of associated psychiatric symptoms.MethodsFifty-eight Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol abuse patients were assessed with a comprehensive battery of reward- and fear-based behavioral tendencies. An 18-item self-report instrument (the Habit, Reward and Fear Scale; HRFS) was employed to quantify affective (fear or reward) and non-affective (habitual) motivations for alcohol use. To characterize clinical and demographic measures associated with habit, reward, and fear, we conducted a partial least squares analysis.ResultsHabitual alcohol use was significantly associated with the severity of alcohol dependence reflected across a range of domains and with lower number of detoxifications across multiple settings. In contrast, reward-driven alcohol use was associated with a single domain of alcohol dependence, reward-related behavioral tendencies, and lower number of detoxifications.ConclusionThese results seem to be consistent with a shift from goal-directed to habit-driven alcohol use with severity and progression of addiction, complementing preclinical work and informing biological models of addiction. Both reward-related and habit-driven alcohol use were associated with lower number of detoxifications, perhaps stemming from more benign course for the reward-related and lack of treatment engagement for the habit-related alcohol abuse group. Future work should further explore the role of habit in this and other addictive disorders, and in obsessive-compulsive related disorders.
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Fairchild, Carter K., Konstantinos V. Floros, Sheeba Jacob, Colin M. Coon, Madhavi Puchalapalli, Bin Hu, Hisashi Harada, et al. "Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA." Cancers 13, no. 10 (May 12, 2021): 2310. http://dx.doi.org/10.3390/cancers13102310.
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Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathognomonic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2-expressing hematological cancers, affords an intriguing therapeutic possibility to treat SS. In addition, there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers, attributing to the limited toxicity of venetoclax. However, preclinical studies of venetoclax in SS have demonstrated an unexpected ineffectiveness. In this study, we analyzed the response of SS to venetoclax and the underlying BCL-2 family biology in an effort to understand venetoclax treatment failure and find a therapeutic strategy to sensitize SS to venetoclax. We found remarkably depressed levels of the endogenous MCL-1 inhibitor, NOXA, in SS compared to other sarcomas. Expressing NOXA led to sensitization to venetoclax, as did the addition of the MCL-1 BH3 mimetic, S63845. Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy.
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Matheson, Justin, Zoe Bourgault, and Bernard Le Foll. "Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review." Biomolecules 12, no. 10 (October 12, 2022): 1462. http://dx.doi.org/10.3390/biom12101462.
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Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMed/Medline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria: eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD; two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC); two found antidepressant-like effects of CBD in males only; and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature.
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Berk, Michael, Sue Jeavons, Olivia M. Dean, Seetal Dodd, Kirsteen Moss, Clarissa S. Gama, and Gin S. Malhi. "Nail-Biting Stuff? The Effect of N-acetyl Cysteine on Nail-Biting." CNS Spectrums 14, no. 7 (July 2009): 357–60. http://dx.doi.org/10.1017/s1092852900023002.
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ABSTRACTN-acetyl cysteine (NAC) is a widely available nutraceutical with a variety of actions. As a precursor of cysteine and glutathione, it has antioxidant properties that may impact on mood and contribute to an effect on impulsivity and obsessive behaviour. Via its additional effect on glutamate via the cystine-glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. Further, by boosting glutathione, NAC acts as a potent antioxidant and has been shown in two positive, large-scale randomized placebo-controlled trials to affect negative symptoms in schizophrenia and depression in bipolar disorder. We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain.
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Duchamp, Olivier, Gael Krysa, Loic Morgand, Hugo Quillery, Robin Artus, Maxime Ramelet, Jeremy Odillard, et al. "Abstract 1654: Mouse models of hepatocellular carcinoma: A comprehensive and functional preclinical platform for immunotherapy research." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1654. http://dx.doi.org/10.1158/1538-7445.am2022-1654.
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Abstract Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death and accounts for over 80% of primary liver cancer worldwide. Early stage HCC can be treated by local ablation, surgical resection or liver transplantation. Systemic pharmacological options are limited (kinase and immune-checkpoint inhibitors). Most cases of liver cancer occur in the setting of chronic liver diseases. Risk factors include chronic Hepatitis B and C, alcohol addiction and metabolic diseases. HCC is a multistep process comprising chronic liver injury, inflammation, fibrosis/cirrhosis and cancer formation. Therefore, providing palliative and curative options remains a high medical need. And with the recent success of immunotherapies in HCC, mouse models that better recapitulate the human disease and antitumor immune response are needed. In order to better evaluate new preventive and curative treatments of liver cancers we developed complementary and integrated strategies to mimic the liver cancer initiation and progression steps in mouse models. These models involve chemotoxic agents, diet-induced disorders and syngeneic or xenogeneic tumor implantation strategies. We established an orthotopic syngeneic model using Hepa1.6 mouse liver hepatoma cells, characterized through liver index, alpha-fetoprotein measurement in serum and liver, and MRI. The response to chemotherapy (sorafenib) and immunotherapy (anti PD-1, anti-TLR) was also assessed and show moderate to high efficiency. Moreover, a panel of xenograft models including Patient-Derived Xenograft models (PDXs) are available to assess new treatment options in human HCC with regards of the genetic mutations and the variety of etiologies seen in human. But as xenograft models are not completely mimicking the human situation of both immune and liver microenvironment, we have recently initiated the development of a double humanized (immune and liver) transgenic mouse as a better host for human tumor engraftment. During the course of HCC formation, the liver undergoes cycles of inflammation, necrosis with regeneration, fibrosis, cell dysplasia and ultimately HCC. Thus, we developed a model induced by a low dose of streptozotocin and high fat diet regimen. In this model, mice develop metabolic syndrome NASH and fibrosis within 12 weeks and HCC within 16 weeks. Of interest, 100% of male mice develop HCC within 16 weeks, in accordance with studies showing that men had a 2-to 7-fold higher risk of developing HCC in human. Treatment of mice with lenvatinib alone or in combination with anti-PD1 increases survival and reduces tumor burden as shown with reduced liver weight/body weight ratio at 16 weeks. Altogether, these results demonstrate the usefulness of this comprehensive platform of preclinical in vivo HCC models to discover and identify novel therapeutic strategies that could circumvent the progression of liver cancers. Citation Format: Olivier Duchamp, Gael Krysa, Loic Morgand, Hugo Quillery, Robin Artus, Maxime Ramelet, Jeremy Odillard, Peggy Provent, Sylvie Maubant, Caroline Mignard, Fabrice Viviani, Samira Benhamouche-Trouillet. Mouse models of hepatocellular carcinoma: A comprehensive and functional preclinical platform for immunotherapy research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1654.
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Matheson, Justin, and Bernard Le Foll. "Therapeutic Potential of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Substance Use Disorders: A Synthesis of Preclinical and Human Evidence." Cells 9, no. 5 (May 12, 2020): 1196. http://dx.doi.org/10.3390/cells9051196.
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Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPAR-α and PPAR-γ isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding. However, the human evidence is limited in scope and has so far been less promising. There have been no published human trials of PPAR agonists for treatment of alcohol use disorder, despite the compelling preclinical evidence. Two trials of PPAR-α agonists as potential smoking cessation drugs found no effect on nicotine-related outcomes. The PPAR-γ agonist pioglitazone showed some promise in reducing heroin, nicotine, and cocaine craving in two human laboratory studies and one pilot trial, yet other outcomes were unaffected. Potential explanations for the discordance between the animal and human evidence, such as the potency and selectivity of PPAR ligands and sex-related variability in PPAR physiology, are discussed.
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Kallupi, Marsida, Song Xue, Bin Zhou, Kim D. Janda, and Olivier George. "An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse." Science Advances 4, no. 10 (October 2018): eaat4751. http://dx.doi.org/10.1126/sciadv.aat4751.
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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 Pseudomonas putida 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.
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Czora-Poczwardowska, Kamila, Radosław Kujawski, Julia Słyńko-Krzyżostaniak, Przemysław Ł. Mikołajczak, and Michał Szulc. "Orexin receptor blockers: A tool for lowering alcohol intake and alcohol addictive behavior in the light of preclinical studies." Postępy Higieny i Medycyny Doświadczalnej 75, no. 1 (January 1, 2021): 959–69. http://dx.doi.org/10.2478/ahem-2021-0007.
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Abstract Alcohol use disorder (AUD) is a severe and globally widespread neurological and psychiatric problem. The treatment with currently used drugs often does not bring the expected effect. New optimization methods or directions in pharmacotherapy are still being sought. The group of bioactive ligands, targeted at neuropeptides called orexins (OXs) and their receptors (OXRs), affects a number of functions including ingestion, sleep-wake regulation, as well as the brain reward system which is the basis of addiction. The purpose of this paper is to systematize the knowledge in the field of preclinical behavioral studies on rodents (rats and mice) in several models of alcohol consumption using the OXRs antagonists. The results of the experiments indicated a potential efficacy of particular OXRs antagonists in the AUD treatment, especially those selectively blocking the OX1R. Among them, SB-334867 in the lowest effective dose of 3 mg/kg i.p. was most studied, as shown in the model of two-bottle choice using C57BL/6 mice. Moreover, this compound did not affect the reduction of cognitive functions. GSK1059865 was also involved in the selective reduction of ethanol intake, and simultaneously did not alter the consumption of sugar solution. The other group of selective OX2R antagonists, such as TCS-OX2-29 and LSN2424100, was less efficient. In summary, the OX1R antagonists proved to have the potential in AUD therapy, not only through the reduction of ethanol consumption but also in the treatment of coexisting behavioral and physiological disorders, such as insomnia and anxiety.
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Maza-Quiroga, Rosa, Nuria García-Marchena, Pablo Romero-Sanchiz, Vicente Barrios, María Pedraz, Antonia Serrano, Raquel Nogueira-Arjona, et al. "Evaluation of plasma cytokines in patients with cocaine use disorders in abstinence identifies transforming growth factor alpha (TGFα) as a potential biomarker of consumption and dual diagnosis." PeerJ 5 (October 12, 2017): e3926. http://dx.doi.org/10.7717/peerj.3926.
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Background Cocaine use disorder (CUD) is a complex health condition, especially when it is accompanied by comorbid psychiatric disorders (dual diagnosis). Dual diagnosis is associated with difficulties in the stratification and treatment of patients. One of the major challenges in clinical practice of addiction psychiatry is the lack of objective biological markers that indicate the degree of consumption, severity of addiction, level of toxicity and response to treatment in patients with CUD. These potential biomarkers would be fundamental players in the diagnosis, stratification, prognosis and therapeutic orientation in addiction. Due to growing evidence of the involvement of the immune system in addiction and psychiatric disorders, we tested the hypothesis that patients with CUD in abstinence might have altered circulating levels of signaling proteins related to systemic inflammation. Methods The study was designed as a cross-sectional study of CUD treatment-seeking patients. These patients were recruited from outpatient programs in the province of Malaga (Spain). The study was performed with a total of 160 white Caucasian subjects, who were divided into the following groups: patients diagnosed with CUD in abstinence (N = 79, cocaine group) and matched control subjects (N = 81, control group). Participants were clinically evaluated with the diagnostic interview PRISM according to the DSM-IV-TR, and blood samples were collected for the determination of chemokine C-C motif ligand 11 (CCL11, eotaxin-1), interferon gamma (IFNγ), interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-17α (IL-17α), macrophage inflammatory protein 1α (MIP-1α) and transforming growth factor α (TGFα) levels in the plasma. Clinical and biochemical data were analyzed in order to find relationships between variables. Results While 57% of patients with CUD were diagnosed with dual diagnosis, approximately 73% of patients had other substance use disorders. Cocaine patients displayed greater cocaine symptom severity when they were diagnosed with psychiatric comorbidity. Regarding inflammatory factors, we observed significantly lower plasma levels of IL-17α (p < 0.001), MIP-1α (p < 0.001) and TGFα (p < 0.05) in the cocaine group compared with the levels in the control group. Finally, there was a significant primary effect of dual diagnosis on the plasma concentrations of TGFα (p < 0.05) in the cocaine group, and these levels were lower in patients with dual diagnoses Discussion IL-17α, MIP-1α and TGFα levels are different between the cocaine and control groups, and TGFα levels facilitate the identification of patients with dual diagnosis. Because TGFα reduction is associated with enhanced responses to cocaine in preclinical models, we propose TGFα as a potential biomarker of complex CUD in humans.
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Unfried, Juan Pablo, Paloma Sangro, Laura Prats-Mari, Bruno Sangro, and Puri Fortes. "The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective." Cancers 13, no. 11 (May 28, 2021): 2651. http://dx.doi.org/10.3390/cancers13112651.
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LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency.
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Westlund, Karin N., and Morgan Zhang. "Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain." Molecules 25, no. 5 (March 3, 2020): 1120. http://dx.doi.org/10.3390/molecules25051120.
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Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood–brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.
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Decroocq, Justine, Rudy Birsen, Jordi Mano, Guillemette Fouquet, Mathilde Gotanègre, Laury Poulain, Sarah Mouche, et al. "Combination of the MEK Inhibitor Trametinib and Pyrvinium Pamoate Efficiently Targets RAS Pathway-Mutated Acute Myeloid Leukemia in Preclinical Models." Blood 134, Supplement_1 (November 13, 2019): 2671. http://dx.doi.org/10.1182/blood-2019-123418.
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While acute myeloid leukemia (AML) is still associated with a low cure rate, recent advances in understanding its molecular complexity have significantly improved therapy for subgroups of patients, including those harboring FLT3, IDH1 or IDH2 mutations1. However, more than half of AML cases still lack a druggable oncogenic target. Human cancers frequently harbor mutations in RAS oncogene family members, including NRAS, KRAS and HRAS, which drive oncogenesis by augmenting cellular proliferation and survival. These are small protein GTPases, regulated by a switch between active GTP-linked and inactive GDP-bound states governed by a complex network of guanine exchange factors (GEFs, favoring RAS-GTP) and GTPase activating factors (GAPs, favoring RAS-GDP). RAS activation - due to either extrinsic recruitment by transmembrane tyrosine kinase receptors or intrinsic mutations - propagates through the downstream RAF/MEK/ERK and PI3K/AKT signaling pathways. Besides RAS-activating mutations conferring independence from physiological regulators, human cancers harbor mutations in other RAS network genes such as NF1 (encoding neurofibromin, a RAS GAP), BRAF or PTPN11 (encoding the SHP2 tyrosine phosphatase involved in RAS activation). Somatic alterations of RAS pathway genes, notably NRAS, KRAS, PTPN11 (missense mutations) and NF1 (mutations and deletions), are reported in up to 20% of AML cases2. Generally arising as late driver events, RAS pathway mutations participate in leukemogenesis through mitogen activated protein kinase (MAPK) activation. The anti-tumor activity of MEK inhibitors in Nras-mutated AML in mice and in some NRAS or KRAS-mutated AML patients suggests that deregulated RAS pathway signaling may represent a bona fide therapeutic target. However, strategies to inhibit RAS - indirectly in most cases - have been hampered by signaling feedback, redundancy and tumor heterogeneity 3. We identified 127 cases of AML with unmet therapeutic need within a cohort from which we excluded those with European leukemia network (ELN) favorable prognosis or FLT3-ITD mutations. Targeted next-generation sequencing revealed RAS pathway alterations in 50 patients (39.3%) and NF1 mutations and deletions, mostly large cytogenetically detected deletions, in 17 (14.8%). NRAS, KRAS, PTPN11, CBL and BRAF variants were detected in 13 (10.4%), 10 (7.9%), 9 (7.2%), 5 (3.9%) and 2 (1.6%) cases, respectively. Mutations in RAF1, RASA1, SOS1 and MAP2K2 were observed in a single case each. RAS pathway alterations appeared in the putative main leukemic clone as well as in subclones inferred from variant allele frequencies. Concurrent RAS pathway mutations were observed in nine cases. Among 79 patients homogeneously treated with intensive induction chemotherapy, RAS pathway alterations correlated with higher clinical proliferation markers (elevated white blood cell count, blast cell percentage and LDH levels) and reduced survival probability, particularly within the ELN intermediate-risk subgroup. We established robust models of RAS/MAPK activation through genetic NF1 disruption or expression of NRASG12D or PTPN11D61Y in growth factor (GF)-dependent cell lines. We assessed oncogenic addiction to the RAS pathway in these cells through GF-independence, increased RAS activity, faster propagation in immunocompromised mice and an exquisite sensitivity to pharmacological MEK inhibition in vitro and in vivo. High-content pharmacological screens with FDA-approved molecules identified pyrvinium pamoate, an anti-helminthic agent, as preferentially active in RAS-activated cells. This compound significantly impaired cell viability and colony formation in primary AML samples with RAS pathway alterations. Moreover, the combination of trametinib and pyrvinium pamoate demonstrated synergy in cell line models and even primary samples. While pyrvinium pamoate strongly inhibited mitochondrial respiration and induced metabolic reprograming towards increased glycolysis, trametinib impaired glycolysis and mitochondrial respiratory capacity, suggesting a mechanistic basis for the synergy observed. These data highlight the translational opportunity in developing pyrvinium pamoate for RAS pathway mutated AML. References 1. Raj RV et al. Leuk. Res. 2018;74:113-120. 2. Simanshu DK et al. Cell. 2017;170(1):17-33. 3.Ryan MB et al. Nat Rev Clin Oncol. 2018;15(11):709-720. Figure Disclosures Hermine: AB Science: Membership on an entity's Board of Directors or advisory committees. Tamburini:Novartis pharmaceutical: Research Funding; Incyte: Research Funding.
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Yao, Hang-Ping, Xiang-Min Tong, and Ming-Hai Wang. "Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110069. http://dx.doi.org/10.1177/17588359211006957.
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Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future.
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Suardi, N. E., M. Preve, M. Godio, E. Bolla, R. A. Colombo, and R. Traber. "Misuse of pregabalin: Case series and literature review." European Psychiatry 33, S1 (March 2016): S312. http://dx.doi.org/10.1016/j.eurpsy.2016.01.1067.
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IntroductionPregabalin is widely used in neurology, psychiatry and primary healthcare, and recently in literature different studies explain the possible misuse [1,2]. Pregabalin has shown greater potency in preclinical models of epilepsy, pain and anxiety, and may have potential in the treatment of cocaine addiction [3]. The purpose of this report is to review the clinical evidence for the potential of abuse and misuse of pregabalin. We propose ten different cases and literature review.MethodTen inpatients with misuse of pregabalin were assessed with: the SCID-P, Anamnestic Folio, HAM-A and DAST. We conducted a systematic review of the literature (PubMed, Embase, PsychInfo), using the terms “pregabalin”, “misuse”.ResultsAll our patients present: cocaine, alcohol and/heroin positive in drugs urine screening at admission; a significant high level of total anxiety at the HAM-A Tot (P < .001), and especially at the item 7 (P < .001); the misuse of pregabalin is made for sniffing; the predominant symptoms assessed were euphoria, psychomotor activation and sedation.Discussion and conclusionSchifano F et al., [1,2] suggest that pregabalin should carefully prescribe in patients with a possible previous history of drug abuse. Our result identifies a particular population the misuse pregabalin that are abuser of cocaine, alcohol and/or heroin. Further research is warranted to replicate our clinical and qualitative observations and, in general, quantitative studies in large samples followed up over time are needed. Methodological limitations, clinical implications and suggestions for future research directions are considered.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Chung, Chia-Min, Tzer-Min Kuo, Kun-Tu Yeh, Chien-Hung Lee, and Ying-Chin Ko. "Reduction in and Preventive Effects for Oral-Cancer Risk with Antidepressant Treatment." Journal of Personalized Medicine 11, no. 7 (June 23, 2021): 591. http://dx.doi.org/10.3390/jpm11070591.
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Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p < 0.05). The drug-reducing effect of AN water in the 1–4-week period was significant in the MAOI group (p < 0.0001) and was also significant in the 3–4-week period in the SSRI group (p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI (p = 0.0081) and MAOI (p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again.
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Kraya, Adam, Run Jin, Chao Zhao, Ariana Familiar, Kathryn Wellen, Adam Resnick, and Ali Nabavizadeh. "TBIO-11. The glutamine transporter and candidate diagnostic and therapeutic target SLC1A5 is associated with subtype-specific metabolic phenotypes and tumor prognosis in pediatric brain cancers." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i185. http://dx.doi.org/10.1093/neuonc/noac079.693.
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Abstract Glutamine transporters play an important role in supporting increased tumor nutritional demands relative to non-cancerous cells, often through overexpression of the solute carrier (SLC) family of membrane transporters. Preclinical studies in adult cancers demonstrate that targeting glutamine addiction via SLC1A5 inhibition results in growth-inhibitory and tumoricidal effects. Given their relatively higher expression in cancer versus normal brain tissue, SLC transporters represent compelling targets for molecularly-targeted radiation and application of available prognostic amino-acid PET imaging probes. However, the role of SLC transporters in pediatric brain cancers has yet to be investigated. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes in ensemble survival models (Reactome: R-HSA-352230), we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Through transcriptome-based consensus clustering, we found that supratentorial, RELA fusion-positive ependymomas and sonic hedgehog-activated medulloblastomas were over-represented among clusters expressing higher levels of SLC1A5 (p = 3.38e-7 and p = 2.18-26, respectively). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 9.8e-4 and p = 0.032) and shorter PFS in LGG (p = 0.022). Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. Our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain cancers that warrant further investigation for molecularly-targeted treatment and amino-acid PET imaging.
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Bach, P., A. Koopmann, and F. Kiefer. "Role of oxytocin in modulating addictive behaviour." European Psychiatry 64, S1 (April 2021): S27. http://dx.doi.org/10.1192/j.eurpsy.2021.99.
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BackgroundThe brain oxytocin system is involved in a wide range of addictive behaviors, inhibiting prime- and cue-induced relapse in preclinical models of substance use disorders. Animal studies linked oxytocin’s effects on drug ingestion to modulation of neurotransmission in the nucleus accumbens (NAc). We set out to investigate whether oxytocin can modulate alcohol cue-induced functional connectivity between the brain reward system and cortical regions.MethodsFifteen male heavy social drinkers were enrolled in a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging study (fMRI) investigating the effect of 24 IU oxytocin on alcohol cue-modulated functional connectivity.ResultsResults of the functional connectivity analyses show that oxytocin application significantly reduced connectivity between the NAc and cuneus and thalamo-occipital connectivity, while enhancing connectivity between the paracingulate gyrus and precentral gyrus (tow-sided seed-level false discovery rate pFDR < 0.05). These effects were specific to the alcohol presentation and were absent during processing of neutral pictures. In addition, the NAc-cuneus connectivity significantly correlated with subjective alcohol cue-induced craving during the scanning session (r = 0.538, p = 0.024). Conclusion: Results provide initial evidence for condition-specific and significant attenuation of NAc connectivity by oxytocin in a sample of heavy social drinkers that was related to lower subjective alcohol craving during the fMRI task. Oxytocin-induced attenuation of NAc connectivity was specific to processing alcohol stimuli and might reflect an attenuation of alcohol-cue saliency by oxytocin that could lead to a reduction of the sensitivity towards the appetitive aspects of alcohol cues.DisclosureNo significant relationships.
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Grigson, Patricia Sue. "Addiction: A preclinical and clinical analysis." Brain Research Bulletin 123 (May 2016): 1–4. http://dx.doi.org/10.1016/j.brainresbull.2016.03.008.
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van der Poll, Tom. "Preclinical Sepsis Models." Surgical Infections 13, no. 5 (October 2012): 287–92. http://dx.doi.org/10.1089/sur.2012.105.
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Panlilio, LV, SR Goldberg, and Z. Justinova. "Cannabinoid abuse and addiction: Clinical and preclinical findings." Clinical Pharmacology & Therapeutics 97, no. 6 (May 2, 2015): 616–27. http://dx.doi.org/10.1002/cpt.118.
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Joscelin, Antonia, Eva Suryani, Yunisa Astiarani, and Satya Joewana. "THE ASSOCIATION BETWEEN ONLINE GAME ADDICTION AND DEPRESSION IN MEDICAL STUDENTS." Jambura Journal of Health Sciences and Research 3, no. 2 (July 31, 2021): 320–28. http://dx.doi.org/10.35971/jjhsr.v3i2.10570.
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The rate of internet use is quite high among college students. Internet is used as a media to play online games, which if played extensively may lead to addiction. Excessive play of online games is found to be associated with decreased psychosocial wellbeing and may cause depressive mood. The rate of depression disorder in Indonesia, especially among college students is quite high. This research aims to find out the association between online game addiction and depression in preclinical students of Atma Jaya Catholic University of Indonesia’s Medicine and Health Science Faculty.This research uses cross-sectional method on preclinical students of Atma Jaya Catholic University of Indonesia’s Medicine and Health Science Faculty year 2017-2019. The instruments used are questionnaires (demographic, Game Addiction Scale, and Patient Health Questionnaire-9). Out of 215 respondents, 3,7% had online game addiction. It was found that the rate of mild depression is 34%, moderate depression is 18.1%, moderately severe depression is 7.4%, and severe depression is 2.3%. Statistical analysis indicates that there is a significant association between online game addiction and depression (p 0,05). In conclusion, there is an association between online game addiction and depression in preclinical students of Atma Jaya Catholic University of Indonesia’s Medicine and Health Science Faculty.
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Hossain, Md Kamal, Majid Davidson, Erica Kypreos, Jack Feehan, Joshua Alexander Muir, Kulmira Nurgali, and Vasso Apostolopoulos. "Immunotherapies for the Treatment of Drug Addiction." Vaccines 10, no. 11 (October 22, 2022): 1778. http://dx.doi.org/10.3390/vaccines10111778.
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Substance use disorders (SUD) are a serious public health concern globally. Existing treatment platforms suffer from a lack of effectiveness. The development of immunotherapies against these substances of abuse for both prophylactic and therapeutic use has gained tremendous importance as an alternative and/or supplementary to existing therapies. Significant development has been made in this area over the last few decades. Herein, we highlight the vaccine and other biologics development strategies, preclinical, clinical updates along with challenges and future directions. Articles were searched in PubMed, ClinicalTrial.gov, and google electronic databases relevant to development, preclinical, clinical trials of nicotine, cocaine, methamphetamine, and opioid vaccines. Various new emerging vaccine development strategies for SUD were also identified through this search and discussed. A good number of vaccine candidates demonstrated promising results in preclinical and clinical phases and support the concept of developing a vaccine for SUD. However, there have been no ultimate success as yet, and there remain some challenges with a massive push to take more candidates to clinical trials for further evaluation to break the bottleneck.
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Sujobert, Pierre, Etienne Paubelle, Adrien Grenier, Florence Zylbersztejn, Mireille Lambert, Laury Poulain, Elizabeth Townsend, et al. "Co-Activation of AMPK and mTORC1 Is Synthetically Lethal in Acute Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 616. http://dx.doi.org/10.1182/blood.v124.21.616.616.
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Abstract Virtually all recurrent molecular alterations in acute myeloid leukemia (AML) functionally converge to cause signal transduction pathway dysregulation that drives cellular proliferation and survival. The mammalian target of rapamycin complex 1 (mTORC1) is a rapamycin-sensitive signaling node defined by the interaction between mTOR and raptor. Constitutive mTORC1 activity is nearly universal in AML. However, pharmacologic inhibition with rapamycin or second-generation mTOR kinase inhibitors has shown limited anti-leukemic activity in both preclinical models as well as patients, suggesting that addiction to this oncogene is not a recurrent event in AML. Here we report that sustained mTORC1 activity is nonetheless essential for the cytotoxicity induced by pharmacologic activation of AMP-activated protein kinase (AMPK) in AML. Our studies employed a novel AMPK activator called GSK621. Using CRISPR and shRNA-mediated silencing of the AMPKa1 catalytic subunit, we showed that AMPK activity was necessary for the anti-leukemic response induced by this agent. GSK621-induced AMPK activation precipitated autophagy, as demonstrated by western blotting, immunofluorescence, flow cytometry and electron microscopy. Blocking autophagy via shRNA-mediated knockdown of ATG5 and ATG7 protected AML cells from cytotoxicity resulting from treatment with GSK621, suggesting that autophagy promotes cell death in the context of active AMPK. GSK621 cytotoxicity was consistently observed across twenty different AML cell lines, primary AML patient samples and AML xenografts in vivo. GSK621-induced AMPK activation also impaired the self-renewal capacity of MLL-ENL- and FLT3-ITD-induced murine leukemias as measured by serial methylcellulose replating assays. Strikingly, GSK621 did not induce cytotoxicity in normal CD34+ hematopoietic progenitor cells. We hypothesized that the differential sensitivity to GSK621 could be due to the difference in amplitude of mTORC1 activation in AML and normal CD34+ cells. In contrast to most reported cellular models in which AMPK inhibits mTORC1 both directly (through raptor phosphorylation) and indirectly (through TSC2 phosphorylation), sustained mTORC1 activity was seen following GSK621-induced AMPK activation in AML. Inhibition of mTORC1 either pharmacologically (using rapamycin) or genetically (using shRNAs targeting raptor and mTOR) abrogated AMPK-induced cytotoxicity in AML cells, including primary AML patient samples. This protective effect was mediated by mTORC1-dependent modulation of the ATF4/CHOP stress response pathway. The ultimate functional consequence was that, rather than diminishing GSK621-induced cytotoxicity, persistent mTORC1 activity was in fact synthetically lethal with AMPK activity in AML cells. This synthetic lethality could be recapitulated in normal CD34+ progenitors by constitutive activation of mTORC1 using a lentivirally-transduced myrAKT construct. It could also be enhanced in AML cells by mTORC1 overactivation induced by CRISPR-mediated deletion of TSC2. Taken together, these data show that the magnitude of mTORC1 activity determines the degree of cytotoxicity triggered by AMPK activation. This finding may have important implications for AMPK and mTORC1 signaling pathways in cancer biology more broadly. Context-dependent permissiveness towards mTORC1 activation may amplify the response to cytotoxic stress, such as that resulting from AMPK activation by GSK621. Our results therefore support AMPK activation as a promising therapeutic strategy in AML and other mTORC1-active malignancies which warrants further investigations in clinical trials. Disclosures Brusq: GSK: Employment. Nicodeme:GSK: Employment.
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Edemann-Callesen, Henriette, Segev Barak, Ravit Hadar, and Christine Winter. "Choosing the Optimal Brain Target for Neuromodulation Therapies as Alcohol Addiction Progresses—Insights From Pre-Clinical Studies." Current Addiction Reports 7, no. 3 (June 12, 2020): 237–44. http://dx.doi.org/10.1007/s40429-020-00316-w.
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Abstract Purpose of the Review Development of addiction involves a transition from reward-driven to habitual behavior, mediated by neuroplastic changes. Based on preclinical findings, this article article reviews the current knowledge on the use of neuromodulation therapies to target alcohol addiction and essentially reduce relapse. Recent Findings To date, only a limited number of preclinical studies have investigated the use of neuromodulation in alcohol addiction, with the focus being on targeting the brain reward system. However, as addiction develops, additional circuits are recruited. Therefore, a differential setup may be required when seeking to alter the chronic alcohol-dependent brain, as opposed to treating earlier phases of alcohol addiction. Summary To promote enduring relapse prevention, the choice of brain target should match the stage of the disorder. Further studies are needed to investigate which brain areas should be targeted by neuromodulating strategies, in order to sufficiently alter the behavior and pathophysiology as alcohol addiction progresses.
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Frigault, Melanie M., Hermes Garban, Joy M. Greer, Stuart Hwang, Raquel Izumi, Amy J. Johnson, Beatrix Stelte-Ludwig, and Ahmed Hamdy. "Abstract 1859: VIP152, a selective CDK9 inhibitor, demonstrates sensitivity in gynecologic cell lines that are cisplatin sensitive or resistant and delivers in vivo antitumor efficacy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1859. http://dx.doi.org/10.1158/1538-7445.am2022-1859.
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Abstract Background: The Myc transcription factor has a short half-life of 20-30 minutes (Ramsay et al. 1984) and oncogenic activation and transcriptional addiction leads to sustained levels of Myc, (Gabay et al. 2014). Mechanisms of activation include MYC gene amplification, mutation or rearrangement and have been reported to be prevalent in gynecologic malignancies, such as serous ovarian (39.2%), uterine (28.1%) and endometrial (19.5%) (https://www.cancer.gov/tcga). Since CDK9 phosphorylation of RNA polymerase II is required for transcription of Myc mRNA, we evaluate VIP152, a highly selective CDK9 inhibitor (Lücking et al 2021), to deliver antitumor responses in preclinical models of gynecologic malignancies. Methods: Gynecologic cell lines were treated with 9 dose levels of VIP152 with DMSO and cisplatin as controls. IC50 were calculated using CellTiter-Glo luminescent cell viability assay after 72 hours treatment. A preliminary analysis of 19 cell lines was undertaken to determine whether response to VIP152 is associated with baseline mutation, gene expression, or copy number variation data. Monotherapy efficacy of VIP152 was evaluated in a cisplatin sensitive A2780 in vivo xenograft mouse model. Results: Screening of gynecologic cell lines demonstrates a 3-log range of sensitivity with VIP152 IC50s ranging from 38-593nM. Simultaneous cisplatin screening identified sensitive and resistant cell lines in the same panel. Low VIP152 IC50s were observed in cell lines sensitive or resistant to cisplatin. Cell lines were assigned as sensitive and resistant based on the VIP152 IC50 values. Preliminary analysis suggests a gene signature could predict response to VIP152 in gynecologic malignancies. VIP152 was evaluated in an ovarian cancer A2780 in vivo xenograft model. Monotherapy treatment with 4 doses of VIP152 across 5 dose levels from 5- to 15-mg/kg weekly regimens provided increasing tumor growth inhibition compared with vehicle control. Conclusions: VIP152 demonstrates sensitivity in gynecologic cell lines independent of cisplatin sensitivity. An interim gene signature that is associated with VIP152 sensitivity was defined and we plan to optimize this signature with a larger cell line panel. Dose-dependent tumor growth inhibition in an in vivo xenograft model is demonstrated. VIP152 is currently being evaluated in the clinic (ClinicalTrials.gov Identifiers: NCT02635672 and NCT04978779). References: Gabay et al. 2014. Cold Spring Harb Perspect Med. 4(6):a014241. Lücking et al. 2021. J Med Chem. 64(15):11651-11674. Ramsay et al. 1984. PNAS. 81(24):7742-7746. Citation Format: Melanie M. Frigault, Hermes Garban, Joy M. Greer, Stuart Hwang, Raquel Izumi, Amy J. Johnson, Beatrix Stelte-Ludwig, Ahmed Hamdy. VIP152, a selective CDK9 inhibitor, demonstrates sensitivity in gynecologic cell lines that are cisplatin sensitive or resistant and delivers in vivo antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1859.
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WILLNER, PAUL. "Animal Models of Addiction." Human Psychopharmacology: Clinical and Experimental 12, S2 (June 1997): S59—S68. http://dx.doi.org/10.1002/(sici)1099-1077(199706)12:2+
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Frazer, Alan, and Francesc Artigas. "Preclinical models of schizophrenia." International Journal of Neuropsychopharmacology 16, no. 10 (November 1, 2013): 2129. http://dx.doi.org/10.1017/s1461145713001181.
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