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Unique Pharmacology,Brain Dysfunction,and Therapeutic Advancements for Fentanyl Misuse and Abuse

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Neuroscience Bulletin 2022年第11期38卷 1365-1382页

作者： Ying Han Lu Cao Kai Yuan Jie Shi Wei Yan Lin Lu National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Peking UniversityBeijing 100191China Peking University Sixth Hospital Peking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)Beijing 100191China Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern institute for Brain Research Peking UniversityBeijing 100871China

Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties.It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere,consequently imposing devastating social,economic,and health burdens worldwide.However,the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown,and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce.This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action,including neural circuit dysfunction and neuroinflammation.We discuss recent progress in the development of pharmacological interventions,anti-fentanyl vaccines,anti-fentanyl/heroin conjugate vaccines,and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression.However,translational studies and clinical trials are still lacking.Considering the present opioid crisis,the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.

关键词： Fentanyl abuse Neural mechanisms Pharmacological interventions Fentanyl vaccines

Association between Alcohol Consumption and Sleep Traits: Observational and Mendelian Randomization Studies in the UK Biobank

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Association between Alcohol Consumption and Sleep Traits: Ob...

Longitudinal Abnormalities in Brain Structure in COVID-19 Patients

中国睡眠研究会第十五届全国学术年会

作者： Junwei Zheng Jie Shi Yan Sun Sizhi Ai National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Peking University The Affiliated Brain Hospital of Guangzhou Medical University

Objective: Previous studies have shown that excessive alcohol consumption is associated with poor sleep.However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits(e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population.To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization(MR) design.Methods: Observational analyses and one-sample MR(linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank(UKB).Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia.Phenotype analyses were externally validated using data from the national Health and Nutrition Examination Survey(2017–2018).Data analysis was conducted from January 2022 to October 2022.The association between alcohol consumption and six self-reported sleep traits(short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia).Results: This study included 383,357 UKB participants(mean [SD] age, 57.0 [8.0] years;46% male) who consumed a mean(SD) of 9.0(10.0) standard drinks(one standard drink equivalent to 14 g of alcohol) per week.In the observational analyses, alcohol consumption was significantly associated with all sleep traits.Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping.In linear MR analyses, a 1-SD(14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold(95% CI, 1.07-1.22) higher risk of snoring(P <.001), a 1.28-fold(95% CI, 1.20-1.37) higher risk of evening chronotype(P <.001) and a 1.24-fold(95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning(P <.001).Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment but s

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Neuroscience Bulletin 2022年第12期38卷 1608-1612页

作者： Xiaoxing Liu Wei Yan Tangsheng Lu Ying Han Lin Lu Peking University Sixth Hospital Peking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)Beijing 100191China National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Peking UniversityBeijing 100191China Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern institute for Brain Research Peking UniversityBeijing 100871China

The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pandemic that began in 2019 has been plaguing our life and society[1]and caused untold deaths worldwide.With the proliferation of COVID-19 vaccines and less lethal strains of the virus,the number of patients with severe COVID-19 has gradually decreased.The majority of patients now exhibit only mild-to-moderate symptoms.

关键词： acute respiratory patients

Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant

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Neuroscience Bulletin 2016年第6期32卷 557-564页

作者： Weili Zhu Zengbo Ding Yinan Zhang Jie Shi Kenji Hashimoto Lin Lu national institute on drug dependence Beijing Key Laboratory of Drug DependencePeking UniversityBeijing 100191 China institute of Mental Health/Peking University Sixth Hospital Key Laboratory of Mental HealthBeijing 100191 China Division of Clinical Neuroscience Chiba University Center for Forensic Mental Health Chiba 260-8670 Japan

Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Con- ventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hin- dered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N- methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast- acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concem. In this review, we focus on the limitations of ketamine, including neurotoicity, cognitive dysfunction, adverse events associated with mental status, psy- chotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associ- ated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine （esketamine） and R-ketamine, are also discussed. R-ketamine has greater antidepressantactions than S-ketamine, without ketamine-related side- effects. Future treatment strategies should consider using R- ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term keta- mine use.

关键词： keywords Antidepressant Ketamine Fast-acting Depression Safety

Prevalence and risk factors of cardiovascular diseases and psychological distress among female scientists and technicians

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2022年第12期23卷 1057-1064页

作者： Lijun ZHANG Yanping BAO Guo LI Shuhui TAO Meiyan LIU Department of Psycho-Cardiology Beijing Anzhen HospitalCapital Medical UniversityBejing 100029China National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Peking UniversityBeijing 100191China School of Public Health Peking UniversityBejing 100191China Henan Medical School Henan UniversityKaifeng 475001China

This study aimed to explore the prevalence and risk factors of cardiovascular disease(CVD)and psychological distress among female scientists and technicians in China.Accordingly,we included scientists and technicians from representative research institutions,medical institutions,colleges,universities,and businesses in China,and the data were collected from July 1,2019 to March 31,2021 via online questionnaires.The parameters evaluated in this study included age,sex,marital status,educational background,monthly income,sleep hours,sleep problems,smoking,alcohol consumption,work-related stress,work burnout,cardiovascular symptoms,CVD,family history,and depressive and anxiety symptoms.A total of 14530 scientists and technicians were included,comprising 7144 men and 7386 women.We found 34.9%men and 16.6%women with CVD,35.1%men and 21.4%women with depressive symptoms,28.7%men and 13.8%women with anxiety symptoms,and 22.0%men and9.5%women with CVD combined with depressive or anxiety symptoms.This study focused on the details of women.Younger women(age≤35 years)had the highest prevalence of depressive symptoms(24.9%),anxiety symptoms(16.2%),and comorbidity(11.2%).It was established that,despite traditional risk factors,unmanageable work burnout,depressive symptoms,and anxiety symptoms were associated with a higher risk of CVD in women;insomnia,overwhelming work stress,unmanageable work burnout,and CVD were linked to a higher risk of depressive symptoms and anxiety;insomnia,overwhelming work stress,and unmanageable work burnout were related to CVD combined with depressive or anxiety symptoms.A bidirectional relationship was noted between CVD and depression or anxiety in female scientists and technicians,and insomnia and overwhelming work stress were positively associated with comorbidity.It is suggested that effective measures should be taken to protect female scientists and technicians from CVD and psychological distress.

关键词： Female scientist and technician Depressive symptom Anxiety Insomnia Cardiovascular disease(CVD)

Online Survey on Accessing Psychological Knowledge and Interventions During the COVID-19 Pandemic-China, 2020

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China CDC weekly 2020年第41期2卷 797-803页

作者： Qingdong Lu Lin Liu Yunhe Wang Le Shi Yingying Xu Zhengan Lu Jianyu Que Jingli Yue Kai Yuan Wei Yan Yankun Sun Jie Shi Yanping Bao Lin Lu National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Peking UniversityBeijingChina School of Public Health Peking UniversityBeijingChina institute of Mental Health National Clinical Research Center for Mental DisordersKey Laboratory of Mental Health and Peking University Sixth HospitalPeking UniversityBeijingChina Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern institute for Brain Research Peking UniversityBeijingChina

Summary What is already known on this topic?The public was at elevated risk of mental health illnesses during the coronavirus disease 2019(COVID-19)pandemic,so accessibility to psychological knowledge and interventions is vital to promptly respond to mental health crises.What is added by this report?During the pandemic period,40,724(71.9%)participants reportedly had access to psychological knowledge,and 36,546(64.5%)participants had accessed information on psychological interventions.Participants who were male,unmarried,living alone,divorced or widowed,or infected with COVID-19 were less likely to access psychological knowledge and intervention.

关键词： COV prompt Access

Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

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Neuroscience Bulletin 2020年第4期36卷 432-448页

作者： Ying Han Kai Yuan Yongbo Zheng Lin Lu national institute of drug dependence and beijing key laboratory of drug dependence Peking UniversityBeijing 100191China Peking University Sixth Hospital Peking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)Beijing 100191China Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern institute for Brain Research Peking UniversityBeijing 100871China

Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors(OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward,emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders,depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists(SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders,whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.

关键词： Orexin Insomnia Depression Anxiety drug addiction

The abuse of anesthetic propofol: associated with cognitive impairment

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Science China(Life Sciences) 2018年第11期61卷 1428-1431页

作者： Weili Zhu Wen Zhang Jiali Li Zengbo Ding Yingjie Huang Lin Lu national institute on drug dependence Peking University institute of Mental Health/Peking University Sixth Hospital and key laboratory of Mental Health Peking University

Propofol (2,6-diisopropylphenol)is a widely used intravenous anesthetic for the fast induction of anesthesia and rapid recovery from general anaesthesia.As a γ-aminobu-tyric acid(GABA)receptor agonist,propofol exerts... 详细信息

关键词： recovery effects fast GABA

The Other Face of the Nucleus Accumbens:Aversion

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Neuroscience Bulletin 2016年第6期32卷 569-571页

作者： Ying Han Lin Lu institute of Mental Health National Clinical Research Center for Mental DisordersKey Laboratory of Mental Healthand Peking University Sixth HospitalPeking University National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Peking University Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern institute for Brain Research Peking University

The nucleus accumbens （NAc） is thought to integrate information that is conveyed by （1） dopaminergic inputs from the midbrain and （2） glutamatergic inputs from limbic and cortical regions, including the amygdala, prefrontal cortex （PFC）, hippocampus, and thalamus [1], and signal to the basal ganglia motor system to guide appropriate behaviors. Addictive drug use is proposed to hijack this system, enhancing the brain＇s reactivity to drug cues and triggering drug-seeking and relapse after prolonged with- drawal [2, 3]. Both positive reinforcement （rewarding effects of drugs） and negative reinforcement （aversive emotional state associated with withdrawal） have been considered to play critical roles in the etiology and main- tenance of drug addiction, and NAc neurons are capable of processing both reward and aversion [4, 5]. Optogenetic activation of inputs from the PFC, ventral hippocampus （vHipp）, and basolateral amygdala （BLA） to the NAc drives positive reinforcement and facilitates reward- seeking behavior [6, 7], but a recent paper in Nature [8] has identified another face of the NAc. The pathway from the paraventricular nucleus of the thalamus （PVT） to the NAc is key to the aversive emotional state of drug withdrawal.

关键词： PVT MSNs