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1.
Adv Pharmacol ; 90: 89-115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706940

RESUMO

Paul Greengard brought to neuroscience the idea of, and evidence for, the role of second messenger systems in neuronal signaling. The fundamental nature of his contributions is evident in the far reach of his work, relevant to various subfields and topics in neuroscience. In this review, we discuss some of Greengard's work from the perspective of nicotinic acetylcholine receptors and their relevance to nicotine addiction. Specifically, we review the roles of dopamine- and cAMP-regulated phospho-protein of 32kDa (DARPP-32) and Ca2+/calmodulin-dependent kinase II (CaMKII) in nicotine-dependent behaviors. For each protein, we discuss the historical context of their discovery and initial characterization, focusing on the extensive biochemical and immunohistochemical work conducted by Greengard and colleagues. We then briefly summarize contemporary understanding of each protein in key intracellular signaling cascades and evidence for the role of each protein with respect to systems and behaviors relevant to nicotine addiction.


Assuntos
Comportamento Aditivo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Nicotina/farmacologia , Transdução de Sinais , Animais , Humanos , Receptores Nicotínicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
J Insect Sci ; 21(2)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33686433

RESUMO

Animals use olfaction to detect developmentally significant volatile organic compounds (VOCs) in their local environment. As part of a wider study aiming to demonstrate that the olfactory responses of animals to VOCs can be modified through the creation of a drug-addicted status and association with a selected VOC, we investigated nicotine and tobacco smoke particulate (TSP) extract as possible addictive compounds for male German cockroaches, Blattella germanica (Linnaeus). In feeding experiments using an artificial food stimulus, food treated with TSP extract was preferred over untreated food. Surprisingly, nicotine, which was expected to be the most important addictive tobacco component, did not induce noticeable effects on cockroach behavior. Both TSP extract and nicotine were shown to be phagostimulants. Olfactometry assays that measured odor-mediated insect behavior demonstrated that male B. germanica did not choose TSP-extract-treated food even when attempts were made specifically to train them via this modality. These results support a hypothesis that B. germanica needs to consume TSP-containing food to show a clear preference for this stimulus and that gustatory mechanisms are involved due to compounds present in the TSP extract.


Assuntos
Blattellidae/efeitos dos fármacos , Estimulantes Ganglionares/farmacologia , Nicotina/farmacologia , Olfato , Tabagismo , Animais , Condicionamento Clássico , Modelos Animais de Doenças , Comportamento Alimentar/efeitos dos fármacos , Masculino , Olfatometria
3.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546289

RESUMO

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine's effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine's effects on energy balance.


Assuntos
Região Hipotalâmica Lateral/metabolismo , Nicotina/farmacologia , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal , Dinorfinas/metabolismo , Metabolismo Energético , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
4.
Psychopharmacology (Berl) ; 238(4): 927-947, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33606060

RESUMO

Adolescence is known for its high level of risk-taking, and neurobiological alterations during this period may predispose to psychoactive drug initiation and progression into more severe use patterns. Stress is a risk factor for drug consumption, and post-weaning social isolation increases drug self-administration in rodents. This review aimed to provide an overview of the effects of adolescent social isolation on cocaine, amphetamine and nicotine use-related behaviours, highlighting the specific period when animals were submitted to stress and these drugs. We wondered if there was a specific period during adolescence that isolation stress would increase drug use vulnerability. A total of 323 publications from the Scopus, Web of Science and PubMed (Medline) electronic databases were identified using the words "social isolation" and "adolescence" and "drug" or "cocaine" or "amphetamine" or "nicotine", resulting in 24 articles after analyses criteria following the PRISMA statement. The main points raised were social isolation during adolescence increased cocaine self-administration, amphetamine and nicotine locomotor activity. We did not observe a pattern of a specific moment during the adolescent period that could lead to an increased vulnerability to drug use. The precise conditions under which adolescent social stress alters drug use parameters are complex and likely depend on several factors.


Assuntos
Anfetamina/farmacologia , Cocaína/farmacologia , Nicotina/farmacologia , Animais , Locomoção/efeitos dos fármacos , Camundongos , Ratos , Autoadministração , Isolamento Social , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
5.
Psychopharmacology (Berl) ; 238(4): 979-990, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33404734

RESUMO

INTRODUCTION: Cognitive function is closely linked to functional outcomes in psychiatric disorders such as schizophrenia, however developing effective treatments for cognitive dysfunction have proven elusive. Potential reasons for this may include the complexity of diseases, the absence of appropriate and translatable animal tests of cognitive dysfunction, and the reproducibility of findings. Attention is a key component of cognitive function traditionally assessed in the clinic using a variant of the continuous performance test (CPT). The 5-choice (5C)-CPT was developed as a translational cross-species version of this task. Given the association between glutamatergic abnormalities and cognitive dysfunction in schizophrenia, we hypothesized that the NMDA receptor antagonist MK-801 would impair 5C-CPT in rats across different laboratories, and determined whether the dopamine D1 receptor agonist SKF38393 or the nonspecific nicotinic agonist nicotine would remediate such deficits. METHOD: Rats were trained in the 5C-CPT at Beacon Discovery and UCSD. These rats were then treated with MK-801, agonist treatment, and combinations of the two. RESULTS: MK-801 produced 5C-CPT deficits in the same domains of rats across sites at similar doses. Neither nicotine nor SKF38393 treatment alone improved performance. Importantly, SKF38393, but not nicotine, remediated the MK-801-induced deficits. CONCLUSION: Convergent observation of MK-801-induced deficits in 5C-CPT was seen across laboratories, resulting in deficits consistent with those seen in people with schizophrenia. Treatment with SKF38393 but not nicotine reversed these deficits. More work is needed, but the 5C-CPT is a reliable method for detecting NMDA receptor disruption-induced deficits in attention.


Assuntos
Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Agonistas Nicotínicos/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Agonistas de Dopamina/farmacologia , Laboratórios , Masculino , Nicotina/farmacologia , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Esquizofrenia/fisiopatologia
6.
Psychopharmacology (Berl) ; 238(3): 845-855, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33410984

RESUMO

RATIONALE: Systemic administration of the tobacco smoke constituent nicotine stimulates brain reward function in rats. However, it is unknown if the inhalation of tobacco smoke affects brain reward function. OBJECTIVES: These experiments investigated if exposure to smoke from high-nicotine SPECTRUM research cigarettes increases reward function and affects the rewarding effects of nicotine in adult male and female Wistar rats. METHODS: Reward function after smoke or nicotine exposure was investigated using the intracranial self-stimulation (ICSS) procedure. A decrease in reward thresholds reflects an increase in reward function. In the first experiment, the rats were exposed to tobacco smoke for 40 min/day for 9 days, and the rewarding effects of nicotine (0.03-0.6 mg/kg) were investigated 3 weeks later. In the second experiment, the dose effects of tobacco smoke exposure (40-min sessions, 1-4 cigarettes burnt simultaneously) on reward function were investigated. RESULTS: Tobacco smoke exposure did not affect the nicotine-induced decrease in reward thresholds or response latencies in male and female rats. Smoke exposure lowered the brain reward thresholds to a similar degree in males and females and caused a greater decrease in latencies in females. There was a positive relationship between plasma nicotine and cotinine levels and the nicotine content of the SPECTRUM research cigarettes. Similar smoke exposure conditions led to higher plasma nicotine and cotinine levels in female than male rats. CONCLUSION: These findings indicate that tobacco smoke exposure enhances brain reward function but does not potentiate the rewarding effects of nicotine in male and female rats.


Assuntos
Encéfalo/efeitos dos fármacos , Nicotina/administração & dosagem , Tempo de Reação/efeitos dos fármacos , Recompensa , Poluição por Fumaça de Tabaco/efeitos adversos , Tabagismo/psicologia , Animais , Cotinina/sangue , Feminino , Masculino , Nicotina/sangue , Nicotina/farmacologia , Ratos , Ratos Wistar , Autoestimulação/efeitos dos fármacos , Tabaco , Tabagismo/sangue
7.
Am J Physiol Renal Physiol ; 320(3): F442-F453, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459165

RESUMO

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users.NEW & NOTEWORTHY In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Nefropatias Diabéticas/metabolismo , Nicotina/farmacologia , Podócitos/metabolismo , Fumar/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Humanos , Camundongos , Podócitos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
8.
Psychopharmacology (Berl) ; 238(4): 1171-1181, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33506304

RESUMO

RATIONALE: There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE ε4 carriers. However, the moderating effects of the APOE ε4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. OBJECTIVE: We sought to determine whether young female carriers of the APOE ε4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. METHODS: We compared parietal P3bs in female chronic smokers with either APOE ε3/ε3 (n = 54) or ε3/ε4 (n = 20) genotype under nicotine-sated conditions and after 12-17-h nicotine deprivation. RESULTS: Nicotine deprivation significantly reduced P3b amplitudes in APOE ε4 carriers, but not in APOE-ε3/ε3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. CONCLUSIONS: The results suggest that subjects with the APOE ε4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.


Assuntos
Apolipoproteína E3/genética , Eletroencefalografia/efeitos dos fármacos , Abandono do Hábito de Fumar/psicologia , Fumar/psicologia , Estimulação Acústica , Adulto , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Lobo Parietal/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Fumar/genética , Adulto Jovem
9.
Food Chem Toxicol ; 149: 112009, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33503469

RESUMO

SARS-CoV-2 is the coronavirus that originated in Wuhan in December 2019 and has spread globally. Studies have shown that smokers are less likely to be diagnosed with or be hospitalized for COVID-19 but, once hospitalized, have higher odds for an adverse outcome. We have previously presented the potential interaction between SARS-CoV-2 Spike glycoprotein and nicotinic acetylcholine receptors (nAChRs), due to a "toxin-like" epitope on the Spike glycoprotein, with homology to a sequence of a snake venom toxin. This epitope coincides with the well-described cryptic epitope for the human anti-SARS-CoV antibody CR3022. In this study, we present the molecular complexes of both SARS-CoV and SARS-CoV-2 Spike glycoproteins, at their open or closed conformations, with the model of the human α7 nAChR. We found that all studied protein complexes' interface involves a large part of the "toxin-like" sequences of SARS-CoV and SARS-CoV-2 Spike glycoproteins and toxin binding site of human α7 nAChR. Our findings provide further support to the hypothesis about the protective role of nicotine and other cholinergic agonists. The potential therapeutic role of CR3022 and other similar monoclonal antibodies with increased affinity for SARS-CoV-2 Spike glycoprotein against the clinical effects originating from the dysregulated cholinergic pathway should be further explored.


Assuntos
/virologia , Epitopos , Nicotina/farmacologia , Vírus da SARS/química , Glicoproteína da Espícula de Coronavírus/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Sequência de Aminoácidos , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Sítios de Ligação de Anticorpos , /prevenção & controle , Humanos , Modelos Moleculares , Agonistas Nicotínicos/química , Agonistas Nicotínicos/uso terapêutico , Sistema Colinérgico não Neuronal , Pandemias , Fatores de Proteção , Conformação Proteica , Homologia de Sequência , Transdução de Sinais , Fumantes , Fumar , Venenos de Serpentes/química
10.
J Pharmacol Exp Ther ; 376(3): 338-347, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33361363

RESUMO

Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for α4ß2* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse. SIGNIFICANCE STATEMENT: Nicotine addiction is a serious public health problem. Cotinine is the major metabolite of nicotine, but its involvement in nicotine reinforcement remains elusive. Our findings indicate that cotinine, at doses producing clinically relevant blood cotinine levels, supported intravenous self-administration in rats. Cotinine self-administration was less robust than nicotine. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results suggest cotinine may play a role in the development of nicotine use and misuse.


Assuntos
Cotinina/administração & dosagem , Cotinina/farmacologia , Nicotina/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Masculino , Mecamilamina/farmacologia , Nicotina/administração & dosagem , Ratos , Ratos Wistar , Receptores Nicotínicos/metabolismo , Autoadministração , Vareniclina/farmacologia
11.
Biomed Pharmacother ; 134: 111135, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33352448

RESUMO

Currently, the clinical treatment of preterm birth, mainly using uterine contraction inhibitors, does not fundamentally reduce the incidence of premature birth (PTB). Premature cervical ripening is an important factor in PTB. We previously found that nicotine-treated pregnant murine had significant cervical resistance to stretch and higher collagen cross-links compared to the control animals, and nicotine prolonged gestation and inhibited cervical ripening. However, the regulatory effects of nicotine on premature cervical ripening and its role in PTB remain unclear. To investigate the effects of nicotine on cervical TGF-ß1/Smad3 pathway and fibroblast-myofibroblast differentiation regulated by this pathway in PTB-like models. Intraperitoneal injection with 15 µg lipopolysaccharide (LPS) in 200 µl PBS into pregnant mice was used to induce the PTB-like model. Mice were randomly divided into four groups: control group, LPS-treated group, LPS + Nicotine co-treated group and LPS + Nicotine+α-BGT co-treated group. Pregnancy outcomes were monitored. The collagen content was assessed by Picrosirius red staining. Expressions of genes and proteins in the TGF-ß/Smad3 pathway were detected by double immunofluorescence staining and quantitative Real-time PCR (qRT-PCR). myofibroblast differentiation were investigated by double immunofluorescence staining and qRT-PCR. Ultrastructures were analyzed by conventional transmission electron microscopy. The rate of PTB and neonatal mortality at birth was significantly higher in the LPS-treated group than in the control group; collagen content also decreased remarkably; the expression of TGF-ß1 in macrophages and p-Smad3 in fibroblasts were reduced; the expression of α-smooth muscle actin (α-SMA, markers for activated fibroblasts) was down-regulated while the expression of calponin and smoothelin (markers for fibroblasts at rest) was up-regulated. Nicotine improved pregnancy outcomes and inhibited collagen degradation, activated the TGF-ß1/Smad3 pathway and promoted cervical fibroblast-myofibroblast differentiation in PTB-like mice; such effects could be reversed by α-bungarotoxin (α-BGT). Nicotine inhibited premature cervical ripening in PTB-like models in relation with up-regulating the TGF-ß/Smad3 pathway and promoting fibroblast to differentiate into myofibroblasts.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Maturidade Cervical/efeitos dos fármacos , Colo do Útero/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Nascimento Prematuro/prevenção & controle , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Actinas/metabolismo , Animais , Colo do Útero/metabolismo , Colo do Útero/ultraestrutura , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/ultraestrutura , Fosforilação , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/metabolismo , Nascimento Prematuro/patologia , Proteólise , Transdução de Sinais
12.
Nicotine Tob Res ; 22(Suppl 1): S35-S44, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320249

RESUMO

INTRODUCTION: Electronic cigarettes (e-cigs) are currently used by millions of adults and adolescents worldwide. Major respiratory symptoms, such as coughing reported by e-cig users, including patients with e-cig, or vaping, product use-associated lung injury (EVALI), indicate e-cig constituent-induced sensory irritation. However, e-cig constituent-induced nociceptive activity in nasal and tracheal respiratory epithelia (RE) and neuronal activation in the trigeminal ganglia and brainstem nuclei, which receive airway chemosensory inputs have not been examined and compared. Comparisons of physiological responses between freebase nicotine and nicotine salts are also missing. AIMS AND METHODS: Event-related potential (ERP) was recorded electrophysiologically to assess mouse nasal and tracheal RE chemosensory responses to various flavorings, nicotine, including freebase and nicotine salts, e-liquid mixtures, and tussigenic stimuli. Also, mice were subjected to inhalation exposure to aerosol of a vanilla-flavored e-liquid or air (control), and the activated-trigeminal nociceptive neurons and brainstem neurons were examined using immunohistochemistry. RESULTS: Individual constituents and mixtures of e-liquids, capsaicin, and citric and acetic acids evoked significantly larger ERP in the nose than in the trachea with the exception of menthol. ERP responses to freebase nicotine were significantly larger than protonated nicotine. Four nicotine salts (benzoate, lactate, levulinate, and salicylate) induced similar responses. Compared with air-exposed mice, e-liquid aerosol-exposed mice showed a significant increase in numbers of activated trigeminal nociceptive neurons and brainstem neurons in the spinal trigeminal nucleus, paratrigeminal nucleus, and nucleus tractus solitarius. CONCLUSIONS: E-liquid constituents region-dependently stimulate airway nociceptive chemosensory systems, and freebase nicotine is more potent than protonated nicotine. IMPLICATIONS: Neural abnormalities have been implicated in the development of nasal and respiratory illnesses. The higher sensitivity of the nasal nociceptive chemosensory system to nicotine and flavorings may indicate a health risk for e-liquid aerosol-induced upper airway illnesses via neurogenic alteration and warrants further investigation.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Aromatizantes/farmacologia , Irritantes/farmacologia , Mucosa Nasal/efeitos dos fármacos , Nicotina/farmacologia , Limiar Sensorial/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Mar Drugs ; 18(12)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339145

RESUMO

Tobacco smoking has become a prominent health problem faced around the world. The α3ß4 nicotinic acetylcholine receptor (nAChR) is strongly associated with nicotine reward and withdrawal symptom. α-Conotoxin TxID, cloned from Conus textile, is a strong α3ß4 nAChR antagonist, which has weak inhibition activity of α6/α3ß4 nAChR. Meanwhile, its analogue [S9K]TxID only inhibits α3ß4 nAChR (IC50 = 6.9 nM), and has no inhibitory activity to other nAChRs. The present experiment investigates the effect of α3ß4 nAChR antagonists (TxID and [S9K]TxID) on the expression and reinstatement of nicotine-induced conditioned place preference (CPP) and explores the behaviors of acute nicotine in mice. The animal experimental results showed that TxID and [S9K] TxID could inhibit the expression and reinstatement of CPP, respectively. Moreover, both had no effect in acute nicotine experiment and the locomotor activity in mice. Therefore, these findings reveal that the α3ß4 nAChR may be a potential target for anti-nicotine addiction treatment. [S9K]TxID, α3ß4 nAChR antagonist, exhibit a superior effect for anti-nicotine addiction, which is promising to develop a novel smoking cessation drug.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Conotoxinas/farmacologia , Nicotina/antagonistas & inibidores , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Animais , Conotoxinas/síntese química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Antagonistas Nicotínicos/síntese química , Receptores Nicotínicos/efeitos dos fármacos
14.
Braz Dent J ; 31(5): 471-476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33146329

RESUMO

Recently, Scardovia wiggsiae has been reported to be strongly associated with caries formation. This study aimed to establish an in vitro model of S. wiggsiae biofilm and to investigate the effect of nicotine on S. wiggsiae colony-forming units (CFUs) growth. S. wiggsiae biofilm was grown overnight using brain-heart infusion (BHI) broth supplemented with 5 g of yeast extract/L (BHI-YE). The overnight culture was used as an inoculum to grow S. wiggsiae biofilm on standardized enamel and dentin samples. Samples were incubated with different nicotine concentrations (0, 0.5, 1, 2, 4, 8, 16 and 32 mg/mL) for 3 days. The dissociated biofilms were diluted, spiral plated on blood agar plates, and incubated for 24 h. CFUs/mL were quantified using an automated colony counter. A two-way ANOVA was used to compare the effect of different nicotine concentrations on S. wiggsiae CFUs. This study demonstrated that S. wiggsiae biofilm could be initiated and formed in vitro. Increased CFUs was observed through 0.5-4 mg/mL and 0.5-8 mg/mL of nicotine using enamel and dentin substrates, respectively. 16 and 32 mg/mL of nicotine were determined as the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC), respectively. S. wiggsiae formed greater biofilm on enamel than dentin specimens in response to the nicotine stimulus. This study demonstrated the negative effect of smoking on increasing S. wiggsiae biofilm. Establishing S. wiggsiae biofilm in vitro may allow researchers in the future to have a better understanding of caries pathogenesis and bacterial interaction.


Assuntos
Cárie Dentária , Nicotina , Actinobacteria , Biofilmes , Esmalte Dentário , Humanos , Nicotina/farmacologia , Streptococcus mutans
15.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L717-L727, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32845704

RESUMO

Most of electronic cigarette (e-cigarette) users are also smoking tobacco cigarettes. Because of the relative novelty of this habit, very little is known on the impact of vaping on pulmonary health, even less on the potential interactions of dual e-cigarette and tobacco cigarette use. Therefore, we used well-established mouse models to investigate the impact of dual exposure to e-cigarette vapors and tobacco cigarette smoke on lung homeostasis. Groups of female BALB/c mice were exposed to room air, tobacco smoke only, nicotine-free flavor-free e-cigarette vapors only or both tobacco smoke and e-cigarette vapors. Moreover, since tobacco smoke and electronic cigarette vapors both affect circadian processes in the lungs, groups of mice were euthanized at two different time points during the day. We found that dual-exposed mice had altered lung circadian gene expression compared with mice exposed to tobacco smoke alone. Dual-exposed mice also had different frequencies of dendritic cells, macrophages, and neutrophils in the lung tissue compared with mice exposed to tobacco smoke alone, an observation also valid for B-lymphocytes and CD4+ and CD8+ T lymphocytes. Exposure to e-cigarette vapors also impacted the levels of immunoglobulins in the bronchoalveolar lavage and serum. Finally, e-cigarette and dual exposures increased airway resistance compared with mice exposed to room air or tobacco smoke alone, respectively. Taken together, these data suggest that e-cigarette vapors, even without nicotine or flavors, could affect how the lungs react to tobacco cigarette smoke exposure in dual users, potentially altering the pathological course triggered by smoking.


Assuntos
Linfócitos B/efeitos dos fármacos , Vapor do Cigarro Eletrônico/efeitos adversos , Fumaça/efeitos adversos , Fumar/efeitos adversos , Animais , Sistemas Eletrônicos de Liberação de Nicotina , Pulmão/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Nicotina/metabolismo , Nicotina/farmacologia
16.
Life Sci ; 261: 118314, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835699

RESUMO

AIMS: Placental tissues from patients with preeclampsia (PE) and in the lipopolysaccharide (LPS)-induced PE-like model were used to investigate the implication of placental inflammation and apoptosis in PE. Whether the beneficial effects of nicotine are related to inhibition of placental inflammation and apoptosis in the PE-like model were investigated. MAIN METHODS: Placental apoptosis was detected in PE patients and the PE-like rat model by TUNEL staining. Changes in the number of CD68+ macrophages in placental tissues from PE patients were detected by immunofluorescent staining. The mRNA expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL-1ß), MCP-1, and proteins involved in extrinsic or intrinsic apoptosis signaling in the PE-like model was determined by qRT-PCR; immunofluorescent staining was used to detect the expression of TNF-α receptor (TNFR1), MCP-1 and apoptosis-related proteins. KEY FINDINGS: Placental apoptosis was increased in both PE patients and the PE-like model, more macrophages infiltrated into placenta in PE patients. A significant upregulation in mRNA expression of TNF-α, IL-1ß, MCP-1, and caspase 3, caspase 8, caspase 9 was found in the PE-like rats compared to the control animals, the immunoreactivity of placental MCP-1, TNFR1, and apoptosis-related proteins (caspase 3, caspase 8, caspase 9, Bax) was also enhanced; nicotine treatment significantly reversed those changes. SIGNIFICANCE: Our data suggests that the protective effects of nicotine are associated with inhibiting placenta inflammation and apoptosis, and nicotine might be a potentially therapeutic candidate for preventing preeclampsia.


Assuntos
Inflamação/tratamento farmacológico , Nicotina/farmacologia , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/prevenção & controle , Adulto , Animais , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Adulto Jovem
17.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L683-L692, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726138

RESUMO

Nicotine of unprecedented concentrations and purity is being inhaled by those using commercially available electronic nicotine delivery systems (ENDS). The consequences of this route of self-administration on the immunological response to inhaled allergens are not known. In mice, sensitization and inhalation challenge with the common environmental house dust mite (HDM) allergen is an experimental model of this response. When mice were exposed to aerosolized nicotine base (aeroNic) twice daily, 5 days/wk for 8 wk, the HDM-induced recruitment of eosinophils (EOS) was substantially reduced as measured in bronchial alveolar lavage fluid (BALF). Oral nicotine administration had no effect. HDM challenge in the presence of nicotinic receptor subtype α7 (α7)-specific type-1 positive allosteric modulators (PAMs) was alone sufficient to suppress EOS. RNA analysis of alveolar macrophages (AM) collected from BALF after HDM challenge of aeroNic revealed that α7 activation strongly suppresses initiation of Ccl24 (eotaxin 2) transcription. To examine possible cellular signaling mechanisms coupling α7 to Ccl24 transcription, an AM culture model system was used. In AM cultures of freshly collected BALF, Ccl24 transcription was robustly activated by a mixture of IL-4 and IL-10, and this was suppressed by coapplication of type-1 PAMs through a pathway that requires p38MAPK but is independent of Jak2. These results suggest that the EOS response to HDM inhaled allergen is subject to modulation through activation of the α7 receptor and suggest that the allergic response may be substantially modified in ENDS users.


Assuntos
Antígenos de Dermatophagoides/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nicotina/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Eosinófilos/metabolismo , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Pulmão/metabolismo , Camundongos , Ácaros , Nicotina/metabolismo , Pyroglyphidae/efeitos dos fármacos , Pyroglyphidae/imunologia
18.
Arterioscler Thromb Vasc Biol ; 40(9): 2054-2069, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640907

RESUMO

OBJECTIVE: Increased CTSS (cathepsin S) has been reported to play a critical role in atherosclerosis progression. Both CTSS synthesis and secretion are essential for exerting its functions. However, the underlying mechanisms contributing to CTSS synthesis and secretion in atherosclerosis remain unclear. Approach and Results: In this study, we showed that nicotine activated autophagy and upregulated CTSS expression in vascular smooth muscle cells and in atherosclerotic plaques. Western blotting and immunofluorescent staining showed that nicotine inhibited the mTORC1 (mammalian target of rapamycin complex 1) activity, promoted the nuclear translocation of TFEB (transcription factor EB), and upregulated the expression of CTSS. Chromatin immunoprecipitation-qualificative polymerase chain reaction, electrophoretic mobility shift assay, and luciferase reporter assay further demonstrated that TFEB directly bound to the CTSS promoter. mTORC1 inhibition by nicotine or rapamycin promoted lysosomal exocytosis and CTSS secretion. Live cell assays and IP-MS (immunoprecipitation-mass spectrometry) identified that the interactions involving Rab10 (Rab10, member RAS oncogene family) and mTORC1 control CTSS secretion. Nicotine promoted vascular smooth muscle cell migration by upregulating CTSS, and CTSS inhibition suppressed nicotine-induced atherosclerosis in vivo. CONCLUSIONS: We concluded that nicotine mediates CTSS synthesis and secretion through regulating the autophagy-lysosomal machinery, which offers a potential therapeutic target for atherosclerosis treatment.


Assuntos
Aterosclerose/tratamento farmacológico , Autofagia/efeitos dos fármacos , Catepsinas/biossíntese , Lisossomos/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nicotina/farmacologia , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Catepsinas/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Exocitose , Lisossomos/enzimologia , Lisossomos/ultraestrutura , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/ultraestrutura , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/ultraestrutura , Via Secretória , Transdução de Sinais , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
19.
Psychopharmacology (Berl) ; 237(8): 2317-2326, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32382782

RESUMO

RATIONALE: Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4ß2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4ß2 receptors, but their in vivo effects are unknown. OBJECTIVES AND METHODS: As α4ß2 nAChRs play an important role in the cognition and the rewarding effects of nicotine, we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT). The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP) was also investigated. RESULTS: In comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-shaped dose-response curve, and their effects were blocked by the co-administration of the antagonist MCL-117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-shaped dose-response curve similar to that of nicotine but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [3H]-epibatidine receptors than [125I]-αBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors. CONCLUSIONS: These behavioural studies indicate that full agonist prolinol aryl ethers are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonist-induced activities.


Assuntos
Aprendizagem em Labirinto/efeitos dos fármacos , Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/metabolismo , Pirrolidinas/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Relação Dose-Resposta a Droga , Éteres/metabolismo , Éteres/farmacologia , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Morfinanos/metabolismo , Morfinanos/farmacologia , Nicotina/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Pirrolidinas/farmacologia , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacologia , Peixe-Zebra
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