RESUMO
Melanin-concentrating hormone (MCH) cells in the hypothalamus regulate fundamental physiological functions like energy balance, sleep, and reproduction. This diversity may be ascribed to the neurochemical heterogeneity among MCH cells. One prominent subpopulation of MCH cells coexpresses cocaine- and amphetamine-regulated transcript (CART), and as MCH and CART can have opposing actions, MCH/CART+ and MCH/CART- cells may differentially modulate behavioral outcomes. However, it is not known if there are differences in the cellular properties underlying their functional differences; thus, we compared the neuroanatomical, electrophysiological, and morphological properties of MCH cells in male and female Mch-cre;L10-Egfp reporter mice. Half of MCH cells expressed CART and were most prominent in the medial hypothalamus. Whole-cell patch-clamp recordings revealed differences in their passive and active membrane properties in a sex-dependent manner. Female MCH/CART+ cells had lower input resistances, but male cells largely differed in their firing properties. All MCH cells increased firing when stimulated, but their firing frequency decreases with sustained stimulation. MCH/CART+ cells showed stronger spike rate adaptation than MCH/CART- cells. The kinetics of excitatory events at MCH cells also differed by cell type, as the rising rate of excitatory events was slower at MCH/CART+ cells. By reconstructing the dendritic arborization of our recorded cells, we found no sex differences, but male MCH/CART+ cells had less dendritic length and fewer branch points. Overall, distinctions in topographical division and cellular properties between MCH cells add to their heterogeneity and help elucidate their response to stimuli or effect on modulating their respective neural networks.
Assuntos
Cocaína , Hormônios Hipotalâmicos , Animais , Feminino , Masculino , Camundongos , Anfetaminas/metabolismo , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Melaninas/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Hormônios Hipofisários/metabolismoRESUMO
Users of novel psychoactive substances (NPS) are at risk, due to limited information about the toxicity and unpredictable effects of these compounds. Wastewater-based epidemiology (WBE) has been used as a tool to provide insight into NPS use at the population level. To understand the preferences and trends of NPS use in Australia, this study involved liquid chromatography mass spectrometry analysis of wastewater collected from Australian states and territories from February 2022 to February 2023. In total, 59 different NPS were included across two complementary analytical methods and covered up to 57 wastewater catchments over the study. The NPS detected in wastewater were 25-B-NBOMe, buphedrone, 1-benzylpiperazine (BZP), 3-chloromethcathinone, N,N-dimethylpentylone (N,N-DMP), N-ethylheptedrone, N-ethylpentylone, eutylone, 4F-phenibut, 2-fluoro deschloroketamine, hydroxetamine, mephedrone, methoxetamine, methylone, mitragynine, pentylone, phenibut, para-methoxyamphetamine (PMA), alpha-pyrrolidinovalerophenone (α-PVP) and valeryl fentanyl. The detection frequency for these NPS ranged from 3 % to 100 % of the sites analysed. A noticeable decreasing trend in eutylone detection frequency and mass loads was observed whilst simultaneously N,N-DMP and pentylone increased over the study period. The emergence of some NPS in wastewater pre-dates other sources of monitoring and provides further evidence that WBE can be used as an additional early warning system for alerting potential NPS use.
Assuntos
Anfetaminas , Drogas Ilícitas , Vigilância Epidemiológica Baseada em Águas Residuárias , Ácido gama-Aminobutírico/análogos & derivados , Austrália , Águas Residuárias , Drogas Ilícitas/análise , Psicotrópicos/análiseRESUMO
Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).
Assuntos
Cocaína , Diabetes Mellitus Tipo 2 , Treinamento Intervalado de Alta Intensidade , Ratos , Masculino , Animais , Proteína Relacionada com Agouti/metabolismo , Neuropeptídeo Y/metabolismo , Leptina/metabolismo , Regulação do Apetite/fisiologia , Pró-Opiomelanocortina/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína Forkhead Box O1/metabolismo , Janus Quinase 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/metabolismo , Ratos Wistar , Hipotálamo/metabolismo , Insulina/metabolismo , Anfetaminas/metabolismo , Cocaína/metabolismo , Citocinas/metabolismoRESUMO
In the quest for winning the game, some athletes take various chemicals (ie, drugs, herbs, or supplements) in attempts to develop greater strength, endurance, or other elements that bring a competitive advantage. There are more than 30,000 chemicals sold throughout the world with unrestrained and unproven claims; however, some athletes consume them with hopes of increasing their athletic abilities, often without knowledge of the potential adverse effects and with limited evidence of efficacy. Complicating this picture is that research on ergogenic chemicals is typically conducted with elite adult male athletes and not with athletes who are in high school. A few of these ergogenic aids include creatine, anabolic androgenic steroids, selective androgen receptor modulators, clenbuterol, androstenedione, dehydroepiandrosterone, human growth hormone, ephedrine, gamma hydroxybutyrate, caffeine, stimulants (amphetamines or methylphenidate), and blood doping. In this article, we describe the purpose of ergogenic aids as well as the potential side effects. [Pediatr Ann. 2023;52(6):e207-e212.].
Assuntos
Estimulantes do Sistema Nervoso Central , Dopagem Esportivo , Esportes , Humanos , Masculino , Criança , Estimulantes do Sistema Nervoso Central/efeitos adversos , Anfetaminas , AtletasRESUMO
O consumo de psicoestimulantes tem crescido exponencialmente, sobretudo entre estudantes de medicina, na busca por aumentar o rendimento acadêmico. Atualmente, a extensa carga horária de aulas e estudos, exigências de produtividade e altos níveis de estresse podem desencadear o uso. Objetivo: Analisar o uso de psicoestimulantes por estudantes do curso de Medicina de um Centro Universitário privado em Minas Gerais. Métodos: Foi realizado um estudo descritivo, quantitativo, com delineamento transversal entre os discentes do 1° ao 5° ano do curso de Medicina no 2° semestre de 2021. Os participantes responderam ao questionário semi-estruturado elaborado pelos autores. Os dados obtidos foram tabulados no software Statistical Product and Service Solutions. Resultados: Dos 244 entrevistados, cerca de 57.4% faziam uso de algum psicoestimulante. Houve maior uso entre os estudantes do 2° ano e as principais substâncias utilizadas foram: cafeína (85%), energético (65%) e metilfenidato (60%). A melhora na concentração (97%) foi o efeito mais percebido pelos usuários, seguido de redução do sono (83%) e melhora de raciocínio (80%). Muitos consideraram que os estimulantes cerebrais têm o potencial de melhorar o rendimento acadêmico, mas pode reduzir a qualidade do sono e consequentemente torná-los susceptíveis a outras enfermidades. Conclusão: É notável que existe uso abusivo de estimulantes cerebrais, sendo fundamental o trabalho em conjunto entre instituição de ensino e familiares, em prol da prevenção e do controle de danos causados por esse hábito
The consumption of psychostimulants has grown exponentially, especially among medical students, in the quest to increase academic performance. Currently, the extensive workload of classes and studies, productivity demands and high levels of stress can trigger use. Objective: To analyze the use of psychostimulants by medical students at a private University Center in Minas Gerais. Methods: A descriptive, quantitative, cross-sectional study was carried out among students from the 1st to the 5th year of the medicine course in the 2nd semester of 2021. The participants answered the semi-structured questionnaire prepared by the authors. The data obtained were tabulated in the Statistical Product and Service Solutions software. Results: Of the 244 respondents, about 57.4% used some psychostimulant. There was greater use among 2nd year students and the main substances used were: caffeine (85%), energy drink (65%) and methylphenidate (60%). Improved concentration (97%) was the effect most perceived by users, followed by reduced sleep (83%) and improved thinking (80%). Many considered that brain stimulants have the potential to improve academic performance, but can reduce sleep quality and consequently make them susceptible to other illnesses. Conclusion: It is notable that there is abusive use of brain stimulants, and it is essential to work together between educational institutions and family members in order to prevent and control the damage caused by this habit
Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Estudantes de Medicina , Desempenho Acadêmico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Atenção/efeitos dos fármacos , Cafeína/efeitos adversos , Consumo de Bebidas Alcoólicas , Paullinia/efeitos adversos , Bebidas Energéticas/efeitos adversos , Anfetaminas/efeitos adversos , Metilfenidato/efeitos adversosRESUMO
Coronary heart disease and its complications remain the most common cause of morbidity and mortality throughout the world. In addition, its incidence among adults <45 years of age has also been steadily increasing in the past few decades. Besides the typical aetiology such as coronary artery abnormalities or autoimmune disorders, increasing rates can be attributed to escalating trends of obesity, type 2 diabetes mellitus, and illicit abuse of drugs such as cocaine and amphetamines in the younger population.1 Every cardiovascular event in a young adult must be thoroughly investigated as the aetiology is typically unconventional. Our case reports a young man who developed an acute inferior wall myocardial infarction (IWMI) in the setting of hyperhomocysteinaemia secondary to vitamin B12-folate deficiency itself due to tropical sprue.
Assuntos
Cocaína , Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Espru Tropical , Humanos , Masculino , Adulto Jovem , Anfetaminas , Ácido Fólico , Infarto do Miocárdio/complicações , Infarto do Miocárdio/etiologia , Espru Tropical/complicações , Vitamina B 12RESUMO
The first paper indicating that a central nervous system stimulant (amphetamine) could be beneficial for children with attention-deficit/hyperactivity disorder (ADHD)-like behavioral symptoms appeared in 1937.1 Over the subsequent 80 years, a range of additional stimulant (methylphenidate) and nonstimulant (atomoxetine, clonidine, guanfacine, and, most recently, viloxazine) drugs have been approved to treat children and adolescents with ADHD. These drug treatments have been the subject of a large number of randomized controlled trails (RCTs). A network meta-analysis found that using clinician ratings, amphetamine, methylphenidate, and atomoxetine were all significantly superior to a placebo.2 These findings suggest that in the short-term at least, these treatments are effective-data are sparse on the efficacy of longer-term drug treatment. However, there are longstanding worries about the use of such drug treatments with children. In particular there are concerns over possible adverse impact on growth. There are also less tangible, but important, concerns of parents as the whether it is appropriate to subject their children to the modification of behavior by drugs.3 For these reasons, there is an urgent need to develop nonpharmacological treatments for children and adolescents with ADHD. One such nonpharmacological treatment is dietary supplementation with micronutrients. In this issue of the Journal, Johnstone et al.4 present a study of micronutrients showing that, under the stringent conditions of an RCT, micronutrients substantially benefit the well-being of young people with ADHD and irritability (risk ratio [RR] = 2.97; 97.5% CI = 1.50-5.90).
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Micronutrientes , Adolescente , Anfetaminas/uso terapêutico , Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Humanos , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Micronutrientes/uso terapêuticoRESUMO
It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.
Assuntos
Ginsenosídeos/farmacologia , Proteína Quinase C-delta/metabolismo , Antagonistas da Serotonina/farmacologia , Síndrome da Serotonina/prevenção & controle , Acetofenonas/farmacologia , Anfetaminas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzopiranos/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Proteína Quinase C-delta/deficiência , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/fisiopatologiaRESUMO
Sports nutrition supplements have previously been reported to contain undeclared doping substances. The use of such supplements can lead to general health risks and may give rise to unintentional doping violations in elite sports. To assess the prevalence of doping substances in a range of high-risk sports nutrition supplements available from Dutch web shops. A total of 66 sports nutrition supplements - identified as potentially high-risk products claiming to modulate hormone regulation, stimulate muscle mass gain, increase fat loss, and/or boost energy - were selected from 21 different brands and purchased from 17 web shops. All products were analyzed for doping substances by the UK life sciences testing company LGC, formerly known as the Laboratory of the Government Chemist, using an extended version of their ISO17025 accredited nutritional supplement screen. A total of 25 out of the 66 products (38%) contained undeclared doping substances, which included high levels of the stimulants oxilofrine, ß-methylphenethylamine (BMPEA) and N,ß-dimethylphenethylamine (NBDMPEA), the stimulant 4-methylhexan-2-amine (methylhexaneamine, 1,3-dimethylamylamine, DMAA), the anabolic steroids boldione (1,4-androstadiene-3,17-dione) and 5-androstene-3ß,17α-diol (17α-AED), the beta-2 agonist higenamine and the beta-blocker bisoprolol. Based upon the recommended dose and the potential variability of analyte concentration, the ingestion of some products identified within this study could pose a significant risk of unintentional doping violations. In addition to inadvertent doping risks, the prescribed use of 3 products (4.5%) could likely impose general health risks.
Assuntos
Suplementos Nutricionais/análise , Dopagem Esportivo , Contaminação de Medicamentos , Agonistas Adrenérgicos beta/análise , Antagonistas Adrenérgicos beta/análise , Alcaloides/análise , Anfetaminas/análise , Androstadienos/análise , Humanos , Prevalência , Medição de Risco , Congêneres da Testosterona/análise , Tetra-Hidroisoquinolinas/análiseRESUMO
BACKGROUND: Weight loss and sports supplements containing deterenol have been associated with serious adverse events including cardiac arrest. OBJECTIVE: To determine the presence and quantity of experimental stimulants in dietary supplements labeled as containing deterenol sold in the United States. METHODS: Dietary supplements available for sale in the US and labeled as containing deterenol or one of its synonyms (e.g., isopropylnorsynephrine and isopropyloctopamine) were purchased online. For each brand, one container or subsample was analyzed by NSF International (Ann Arbor, MI) and one container or subsample by the Netherland's National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands). When differences existed between the two containers or subsamples of the same brand, both products were reanalyzed by Sciensano (Brussels, Belgium). NSF International carried out qualitative and quantitative analyses using ultra-high-performance liquid chromatography (UHPLC) quadrupole-Orbitrap mass spectrometry. RIVM performed qualitative and quantitative analysis using UHPLC quadrupole time-of-flight mass spectrometry. Sciensano carried out qualitative analysis using UHPLC quadrupole-Orbitrap mass spectrometry. RESULTS: Seventeen brands of supplements were analyzed. Many brands included more than one prohibited stimulant in the same product: 4 brands (24%, 4/17) included 2 stimulants, 2 (12%, 2/17) combined 3 stimulants, and 2 (12%, 2/17) combined 4 stimulants. The range of quantities per recommended serving size of the 9 stimulants detected were 2.7 mg to 17 mg of deterenol; 1.3 mg to 20 mg of phenpromethamine (Vonedrine); 5.7 mg to 92 mg of beta-methylphenylethylamine (BMPEA); 18 mg to 73 mg of octodrine; 18 mg to 55 mg of oxilofrine; 48 mg of higenamine; 17 mg of 1,3-dimethylamylamine (1,3-DMAA); 1.8 mg to 6.6 mg of 1,3-dimethylbutylamine (1,3-DMBA); and 5.3 mg of 1,4-dimethylamylamine (1,4-DMAA). CONCLUSION: Weight loss and sports supplements listing deterenol as an ingredient contained 9 prohibited stimulants and 8 different mixtures of stimulants, with as many as 4 experimental stimulants per product. These cocktails of stimulants have never been tested in humans and their safety is unknown.
Assuntos
Agonistas Adrenérgicos/análise , Fármacos Antiobesidade/análise , Estimulantes do Sistema Nervoso Central/análise , Suplementos Nutricionais/análise , Agonistas Adrenérgicos/efeitos adversos , Alcaloides/análise , Aminas/análise , Anfetaminas/análise , Fármacos Antiobesidade/efeitos adversos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Qualidade de Produtos para o Consumidor , Suplementos Nutricionais/efeitos adversos , Efedrina/análogos & derivados , Efedrina/análise , Heptanos/análise , Humanos , Octopamina/análogos & derivados , Octopamina/análise , Medição de Risco , Tetra-Hidroisoquinolinas/análise , Estados UnidosRESUMO
OBJECTIVE: The assessment of clinical efficacy and toxicity is very important in pharmacology and toxicology. The effects of psychostimulants (e.g. amphetamine), psychotomimetics (e.g. Cannabis sativus) and snake antivenoms are sometimes unpredictable even at lower doses, leading to serious intoxication and fatal consequences. Hence, there is need to re-assess some formulas for calculation of therapeutic index, lethal time and safety margin with a view to identifying therapeutic agents with remarkable toxicity potentials. RESULTS: The therapeutic index formula [Formula: see text] was derived from T1 = LD50/ED50 and ED50 = [Formula: see text]. Findings have shown that, therapeutic index is a function of death reversal (s), safety factor (10-4) and weight of animal (Wa). However, the new safety margin formula [Formula: see text] derived from LT50 = [Formula: see text] and MS = [Formula: see text] shows that safety margin is a function of cube root of ratio between LT50 and LD50 and ED100th. Concentration (k) of toxicant at the receptor [Formula: see text] derived from D1 × Tn = K and LD1 = [Formula: see text] shows that therapeutic index, lethal time and safety margin is a function of drug or toxicant concentration at the receptor, the drug-receptor interaction and dose of toxicant or drug administered at a particular time.
Assuntos
Abrus , Anfetaminas/farmacologia , Anti-Infecciosos/farmacologia , Antivenenos/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Serotoninérgicos/farmacologia , Venenos de Serpentes/toxicidade , Serpentes , Índice Terapêutico , Animais , Dronabinol/farmacologia , Humanos , Dose Letal Mediana , Dietilamida do Ácido Lisérgico/farmacologia , Permanganato de Potássio/farmacologiaRESUMO
Increasing reports of neurological and psychiatric complications due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the precise mechanism of SC toxicity is unclear. This paucity of understanding highlights the need to investigate the in-vitro toxicity and mechanistic pathways of three SCs: butylone, pentylone, and 3,4-Methylenedioxypyrovalerone (MDPV). Human neuronal cells of SH-SY5Y were cultured in supplemented DMEM/F12 media and differentiated to a neuronal phenotype using retinoic acid (10 µM) and 12-O-tetradecanoylphorbol-13-acetate (81 nM). Trypan blue and lactate dehydrogenase assays were utilized to assess the neurotoxicity potential and potency of these three SCs. To investigate the underlying neurotoxicity mechanisms, measurements included markers of oxidative stress, mitochondrial bioenergetics, and intracellular calcium (Ca2+), and cell death pathways were evaluated at two doses (EC15 and EC40), for each drug tested. Following 24 h of treatment, all three SCs exhibited a dose-dependent neurotoxicity, characterized by a significant (p < 0.0001 vs. control) production of reactive oxygen species, decreased mitochondrial bioenergetics, and increased intracellular Ca2+ concentrations. The activation of caspases 3 and 7 implicated the orchestration of mitochondrial-mediated neurotoxicity mechanisms for these SCs. Identifying novel therapeutic agents to enhance an altered mitochondrial function may help in the treatment of acute-neurological complications arising from the illicit use of these SCs.
Assuntos
Alcaloides/farmacologia , Neurônios Dopaminérgicos/citologia , Mitocôndrias/metabolismo , Trifosfato de Adenosina/metabolismo , Alcaloides/química , Anfetaminas/química , Anfetaminas/farmacologia , Benzodioxóis/química , Benzodioxóis/farmacologia , Cálcio/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Metabolismo Energético , Homeostase/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Pirrolidinas/química , Pirrolidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Catinona SintéticaAssuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Anfetaminas/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Anfetaminas/administração & dosagem , Anfetaminas/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Terapia Comportamental , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Criança , Pré-Escolar , Preparações de Ação Retardada , Humanos , Metilfenidato/administração & dosagem , Metilfenidato/efeitos adversos , Estimulação Elétrica Nervosa TranscutâneaRESUMO
Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse's head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR's pharmacology and its characteristic behavioral outputs in rodents.
Assuntos
Anfetaminas/farmacologia , Alucinógenos/farmacologia , Movimentos da Cabeça/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/instrumentação , Desenho de Equipamento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 5-HT2A de Serotonina/genéticaRESUMO
Much evidence demonstrates the antinociceptive effect of magnetic fields (MFs). However, the analgesic action mechanism of the electromagnetic field (EMF) is not exactly understood. The aim of the present study was to investigate the effects of 5-HT1 and 5-HT2 receptor agonists (serotonin HCl and 2,5-dimethoxy-4-iodoamphetamine [DOI] hydrochloride) on EMF-induced analgesia. In total, 66 adult male Wistar albino rats with an average body mass of 225 ± 13 g were used in this study. The animals were subjected to repeated exposures of alternating 50 Hz and 5 mT EMF for 2 h a day for 15 days. Prior to analgesia tests, serotonin HCl (5-HT1 agonist) 4 mg/kg, WAY 100635 (5-HT1 antagonist) 0.04 mg/kg, DOI hydrochloride (5-HT2 receptor agonist) 4 mg/kg, and SB 204741 (5-HT2 antagonist) 0.5 mg/kg doses were injected into rats. For statistical analysis of the data, analysis of variance was used and multiple comparisons were determined by Tukey's test. Administration of serotonin HCl MF (5 mT)-exposed rats produced a significant increase in percent maximal possible effect (% MPE) as compared with EMF group (P < 0.05). On the contrary, injection of WAY 100635 to MF-exposed rats produced a significant decrease in analgesic activity (P < 0.05). Similarly, the administration of DOI hydrochloride significantly increased % MPE values as compared with the EMF group while SB 204741 reduced it (P < 0.05). In conclusion, our results suggested that serotonin 5-HT1 and 5-HT2 receptors play an important role in EMF-induced analgesia; however, further research studies are necessary to understand the mechanism. Bioelectromagnetics. 2019;40:319-330. © 2019 Bioelectromagnetics Society.
Assuntos
Anfetaminas/farmacologia , Analgesia , Campos Eletromagnéticos , Agonistas do Receptor de Serotonina/farmacologia , Anfetaminas/química , Animais , Masculino , Manejo da Dor , Ratos Wistar , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/químicaRESUMO
ß-Methylphenethylamine [(BMPEA), 2-phenylpropan-1-amine] is a structural isomer of amphetamine (1-phenylpropan-2-amine) that has been identified in preworkout and weight loss supplements, yet little information is available about its pharmacology. Here, the neurochemical and cardiovascular effects of BMPEA and its analogs, N-methyl-2-phenylpropan-1-amine (MPPA) and N,N-dimethyl-2-phenylpropan-1-amine (DMPPA), were compared with structurally related amphetamines. As expected, amphetamine and methamphetamine were potent substrate-type releasing agents at dopamine transporters (DATs) and norepinephrine transporters (NETs) in rat brain synaptosomes. BMPEA and MPPA were also substrates at DATs and NETs, but they were at least 10-fold less potent than amphetamine. DMPPA was a weak substrate only at NETs. Importantly, the releasing actions of BMPEA and MPPA were more potent at NETs than DATs. Amphetamine produced significant dose-related increases in blood pressure (BP), heart rate (HR), and locomotor activity in conscious rats fitted with surgically implanted biotelemetry transmitters. BMPEA, MPPA, and DMPPA produced increases in BP that were similar to the effects of amphetamine, but the compounds failed to substantially affect HR or activity. The hypertensive effect of BMPEA was reversed by the α-adrenergic antagonist prazosin but not the ganglionic blocker chlorisondamine. Radioligand binding at various G protein-coupled receptors did not identify nontransporter sites of action that could account for cardiovascular effects of BMPEA or its analogs. Our results show that BMPEA, MPPA, and DMPPA are biologically active. The compounds are unlikely to be abused due to weak effects at DATs, but they could produce adverse cardiovascular effects via substrate activity at peripheral NET sites.
Assuntos
Anfetaminas/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais/efeitos adversos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Animais , Frequência Cardíaca/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , TemperaturaRESUMO
OBJECTIVE: Tourette syndrome (TS) is a chronic neuropsychiatric disorder. Its clinical manifestations are involuntary and recurrent muscle twitch, resulting in motor twitch and occurrence twitch. Traditional Chinese medicine has obvious advantages in treating TS. The aim of this study was to investigate the effects and mechanism of gastrodin on 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced TS in rats. METHODS: TS model was induced by DOI. Behaviors in TS rats were detected. The striatum, serum inflammatory factors interleukin-6, interleukin-1ß, and tumor necrosis factor-a were detected by enzyme-linked immunosorbent assay. Western blot technique was used to detect the expressions of TLR/NF-κB and TLR/MAPK signaling pathways in the striatum. RESULTS: Gastrodin can significantly improve behavioral changes of TS rats induced by DOI, reduce inflammatory factors in serum and striatum in TS rats, and inhibit activation of TLR/NF-κB and TLR/MAPK signaling in striatum in TS rats. CONCLUSION: Gastrodin can significantly relieve the TS induced by DOI in rats. Its mechanism is related to the inhibition of striatal TLR/NF-κB and TLR/MAPK signaling activation.
Assuntos
Anfetaminas/toxicidade , Comportamento Animal/efeitos dos fármacos , Álcoois Benzílicos/farmacologia , Glucosídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Síndrome de Tourette/tratamento farmacológico , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Síndrome de Tourette/induzido quimicamente , Síndrome de Tourette/metabolismo , Síndrome de Tourette/patologiaRESUMO
Khat (Catha edulis Forsk) is a narcotic plant which contains significant amounts of amphetamines, like alkaloids. Herein, analysis of the essential oil composition showed that Khat has useful volatile chemicals in addition to its alkaloids. Results indicated that among 35 identified constituents including mono and sesquiterpenes, the diterpene kaurene, comprises the major part of the essential oil, around 50 percent of total. Kaurene is known as a potent biological agent for the treatment of cancer patients. The presence of kaurene at high levels indicates that the essential oil of Catha edulis can potentially be more effectively exploited rather than its narcotic stimulant amphetamine-like alkaloids.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Catha/química , Diterpenos do Tipo Caurano/análise , Entorpecentes/química , Óleos Voláteis/química , Alcaloides/análise , Anfetaminas , Antineoplásicos Fitogênicos/química , Humanos , Óleos Voláteis/análise , Extratos Vegetais/análiseRESUMO
For centuries, a large number of people living in the southwestern part of the Arabian Peninsula and eastern Africa have chewed the fresh leaves and twigs of the plant Catha edulis Forsk, more commonly known as khat, for its psychostimulatory effect. The main active compound in khat is cathinone, whose synthetic derivatives form a part of the new psychoactive substances list. This review summaries the prevalence of khat use, its harvesting and consumption, the biosynthetic pathway in khat, the mechanism of action, the results from animal and human studies, and its dependence potential. It is unlikely that khat use will be prohibited in countries where it is traditionally consumed and socially acceptable unlike in other countries of the world where both the importation and the consumption of khat and cathinone is banned. Khat users being mainly Muslims prohibited from using alcohol or other drugs probably represent the largest global number of mono-drug users of an amphetamine-like stimulant. Thus, khat use represents a unique situation and a neglected area of research in Africa.
Assuntos
Catha/efeitos adversos , Catha/fisiologia , África/epidemiologia , Alcaloides/farmacologia , Anfetaminas/farmacologia , Arábia/epidemiologia , Humanos , Mastigação , Extratos Vegetais/farmacologiaRESUMO
In this study the occurrence and the behavior of illicit drugs and their metabolites have been investigated for two wastewater treatment plants (WWTPs) (namely, WWTP-1 and WWTP-2) located in Sicily (island of Italy). Samples were analyzed for methamphetamine, cocaine (COC), 3,4-methylenedioxymethamphetamine (MDMA), methadone (METH), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 3,4-methylenedioxy amphetamine (MDA); 3,4-methylenedioxy ethylamphetamine (MDEA), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) and Benzoylecgonine (BEG). The BEG, COC, MOR and THC-COOH were found at the highest concentration in both WWTPs. The Wastewater-based epidemiology calculation for BEG, COC, cannabinoids and THC-COOH was performed. On average, for both plants, population consumes 1.6 and 23.4 dose 1000 inh-1 day-1 of cocaine and cannabis, respectively. For WWTP-1 negative removals of illicit drugs were observed. For WWTP-2 the following average removal efficiencies were obtained: BEG (77.85%), COC (92.34%), CODEINE (64.75%), MOR (90.16%) and THC-COOH (68.64%).