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Humanos , Masculino , Femenino , Tabaquismo/tratamiento farmacológico , Cese del Hábito de Fumar , Fumar Cigarrillos/tratamiento farmacológico , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Alcaloides de Quinolizidina/administración & dosificación , Síndrome de Abstinencia a Sustancias/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Nicotínicos/efectos de los fármacos , Resultado del Tratamiento , Agentes para el Cese del Hábito de Fumar/efectos adversos , Duración de la Terapia , Alcaloides de Quinolizidina/efectos adversos , Nicotina/antagonistas & inhibidoresRESUMEN
Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.
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Fumar Cigarrillos , Alcaloides de Quinolizidina , Agentes para el Cese del Hábito de Fumar , Cese del Hábito de Fumar , Tabaquismo , Humanos , Persona de Mediana Edad , Alcaloides , Azocinas , Duración de la Terapia , Quinolizinas , Cese del Hábito de Fumar/métodos , Tabaquismo/tratamiento farmacológico , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Agentes para el Cese del Hábito de Fumar/efectos adversos , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Método Doble Ciego , Resultado del Tratamiento , Masculino , Femenino , Alcaloides de Quinolizidina/administración & dosificación , Alcaloides de Quinolizidina/efectos adversos , Alcaloides de Quinolizidina/farmacocinética , Alcaloides de Quinolizidina/uso terapéutico , Nicotina/antagonistas & inhibidores , Receptores Nicotínicos/efectos de los fármacos , Fumar Cigarrillos/tratamiento farmacológicoRESUMEN
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.
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Condicionamiento Operante/efectos de los fármacos , Conotoxinas/farmacología , Nicotina/antagonistas & inhibidores , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Animales , Conotoxinas/síntesis química , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Antagonistas Nicotínicos/síntesis química , Receptores Nicotínicos/efectos de los fármacosRESUMEN
INTRODUCTION: Behavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release. OBJECTIVE: The aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization. METHODS: In the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV. RESULTS: Taken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum. CONCLUSION: The behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS.
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Adenosina/antagonistas & inhibidores , Conducta Animal/efectos de los fármacos , Derivados del Benceno/farmacología , Nicotina/antagonistas & inhibidores , Antagonistas Nicotínicos/farmacología , Sulfonamidas/farmacología , Adenosina/metabolismo , Administración Oral , Animales , Derivados del Benceno/administración & dosificación , Derivados del Benceno/síntesis química , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos BALB C , Nicotina/administración & dosificación , Antagonistas Nicotínicos/administración & dosificación , Antagonistas Nicotínicos/síntesis química , Sulfonamidas/administración & dosificación , Sulfonamidas/síntesis químicaRESUMEN
BACKGROUND: Cigarette smoking or nicotine replacement therapy has been associated with cardiometabolic disorders (CMD). Hyperuricemia has been implicated in the pathogenesis of CMD and cardiorenal dysfunction. Gut microbiota-derived short chain fatty acids (SCFAs) have been reported to have beneficial glucoregulatory and cardiorenal protective effects. This study aimed at investigating the effect of acetate, a gut-derived SCFA, on nicotine-induced CMD and associated cardiorenal dysmetabolism. MATERIALS AND METHOD: Twenty-four male Wistar rats (n = 6/group) were grouped as: vehicle (p.o.), nicotine-exposed (1.0 mg/kg; p.o.), and sodium acetate-treated (200 mg/kg; p.o.) with or without nicotine exposure daily for 6 weeks. Glucose regulation was evaluated by oral glucose tolerance test and homeostatic model assessment of insulin resistance. Cardiac and renal triacylglycerol (TG), lactate, nitric oxide (NO), uric acid (UA) levels, lactate dehydrogenase (LDH), creatine kinase (CK), adenosine deaminase (ADA), and xanthine oxidase (XO) activities were measured. RESULTS: The CMD were confirmed in the nicotine-exposed rats that exhibited lower body weight, insulin resistance, endothelial dysfunction, glucose intolerance, increased cardiac and renal TG, TG/HDL-cholesterol, UA, lactate, lipid peroxidation, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, LDH, CK, ADA and XO activities. Concurrent treatment with acetate prevented nicotine-induced glucometabolic and cardiorenal alterations. CONCLUSION: In summary, these results implied that nicotine exposure caused glucometabolic dysregulation and surplus lipid deposit in the heart and kidney through increased UA production and CK activity. Therefore, oral acetate administration prevents cardiorenal lipotoxicity and glucometabolic dysregulation via suppression of UA production and CK activity in nicotine-exposed rats.
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Creatina Quinasa/metabolismo , Corazón/efectos de los fármacos , Riñón/efectos de los fármacos , Redes y Vías Metabólicas/efectos de los fármacos , Miocardio/metabolismo , Nicotina/efectos adversos , Acetato de Sodio/farmacología , Ácido Úrico/metabolismo , Animales , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Riñón/metabolismo , Masculino , Nicotina/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.
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Ansiolíticos/farmacología , Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Benzoatos/farmacología , Nicotina/antagonistas & inhibidores , Antagonistas Nicotínicos/farmacología , Pirrolidinas/farmacología , Receptores Nicotínicos/metabolismo , Recompensa , Animales , Ansiedad/inducido químicamente , Modelos Animales de Enfermedad , Nicotina/administración & dosificación , Receptores Nicotínicos/genética , Natación , Pez CebraRESUMEN
Nicotine is the primary psychoactive chemical in both traditional and electronic cigarettes (e-cigarettes). Nicotine levels in both traditional cigarettes and e-cigarettes are an important concern for public health. Nicotine exposure due to e-cigarette use is of importance primarily due to the addictive potential of nicotine, but there is also concern for nicotine poisoning in e-cigarette users. Nicotine concentrations in e-liquids vary widely. Additionally, there is significant genetic variability in the rate of metabolism of nicotine due to polymorphisms of CYP2A6, the enzyme responsible for the metabolism of approximately 80% of nicotine. Recent studies have shown CYP2A6 activity is also reduced by aromatic aldehydes such as those added to e-liquids as flavoring agents, which may increase nicotine serum concentrations. However, the impacts of flavored e-liquids on CYP2A6 activity are unknown. In this study, we investigated the impact of three flavored e-liquids on microsomal recombinant CYP2A6. Microsomal recombinant CYP2A6 was challenged at e-liquid concentrations ranging up to 0.125% (v/v) and monitored for metabolic activity using a probe molecule approach. Two e-liquids exhibited dose-dependent inhibition of CYP2A6 activity. Mass spectrometry was conducted to identify flavoring agents in flavored e-liquids that inhibited CYP2A6. Microsomal recombinant CYP2A6 was subsequently exposed to flavoring agents at concentrations ranging from 0.03 µM to 500 µM. Cinnamaldehyde and benzaldehyde were found to be the most potent inhibitors of microsomal CYP2A6 of the flavoring agents tested, with identified IC50 values of 1.1 µM and 3.0 µM, respectively. These data indicate certain aromatic aldehyde flavoring agents are potent inhibitors of CYP2A6, which may reduce nicotine metabolism in vivo. These findings indicate an urgent need to evaluate the effects of flavoring agents in e-cigarette liquids on the pharmacokinetics of nicotine in vivo.
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Citocromo P-450 CYP2A6/antagonistas & inhibidores , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistemas Electrónicos de Liberación de Nicotina , Aromatizantes/farmacología , Nicotina/antagonistas & inhibidores , Vapeo , Citocromo P-450 CYP2A6/metabolismo , Inhibidores Enzimáticos del Citocromo P-450/análisis , Relación Dosis-Respuesta a Droga , Aromatizantes/análisis , Humanos , Espectrometría de Masas , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Conformación Molecular , Nicotina/metabolismo , Proteínas Recombinantes/metabolismoRESUMEN
BACKGROUND: Adenosine A2a receptors form a mutually inhibitory heteromeric complex with dopamine D2 receptors such that each receptor exhibits lower sensitivity to its agonist after the opposing receptor agonist is bound. This study analyzed the effects of CGS 21680, an adenosine A2A agonist, on nicotine conditioned place preference (CPP) in adolescence using a rodent model of schizophrenia (SZ). METHODS: Rats were treated from postnatal day (P) 1 to P21 with saline or the dopamine D2/D3 agonist quinpirole (NQ treatment) and raised to P41. After an initial preference test, rats were conditioned with saline or nicotine (0.6 mg/kg base) from P43 to P51. CGS 21680 (0.03 or 0.09 mg/kg) was given 15 minutes before nicotine was administered. The post-conditioning test was administered on P52. On P53, the nucleus accumbens (NAcc) was analyzed for brain-derived neurotrophic factor (BDNF) and glial cell-lined neurotrophic factor (GDNF). RESULTS: Results revealed that NQ treatment enhanced nicotine CPP, and both doses of CGS 21680 alleviated this enhancement. Nicotine also resulted in a CPP in controls, which was alleviated by both doses of CGS 21680. BDNF closely followed the behavioral results: CGS 21680 alleviated the enhancement in NAcc BDNF in NQ-treated animals, and eliminated the increase in NAcc BDNF produced by nicotine in controls. NQ-treated animals conditioned to nicotine resulted in an increase of NAcc GDNF, but this was eliminated by CGS 21680. Both BDNF and GDNF correlated with CPP performance. CONCLUSIONS: Results revealed that an adenosine A2A agonist decreased the rewarding aspects of nicotine and its accompanying neural plasticity changes in a model of SZ.
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Adenosina/análogos & derivados , Condicionamiento Psicológico/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nicotina/farmacología , Fenetilaminas/farmacología , Recompensa , Esquizofrenia/metabolismo , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Masculino , Nicotina/antagonistas & inhibidores , Núcleo Accumbens/metabolismo , Quinpirol , Ratas , Esquizofrenia/inducido químicamenteRESUMEN
Noradrenergic projections from the nucleus tractus solitarius (NTS) to the hypothalamic paraventricular nucleus (PVN) are involved in nicotine (Nic) dependence. Nic induces hypothalamic norepinephrine (NE) release through N-methyl-d-aspartate receptors (NMDARs) and nitric oxide in the NTS. However, acupuncture attenuates Nic withdrawal-induced anxiety. Therefore, this study investigated the effects of acupuncture on Nic-induced hypothalamic NE release. Rats received an intravenous infusion of Nic (90 µg/kg, over 60 s) and extracellular NE levels in the PVN were determined by in vivo microdialysis. Immediately after Nic administration, the rats were bilaterally treated with acupuncture at acupoint HT7 (Shen-Men) or PC6 (Nei-Guan), or a non-acupoint (tail) for 60 s. Acupuncture at HT7, but not at PC6 or the tail, significantly reduced Nic-induced NE release. However, this was abolished by a post-acupuncture infusion of either NMDA or sodium nitroprusside into the NTS. Additionally, acupuncture at HT7, but not the control points, prevented Nic-induced plasma corticosterone secretion and inhibited Nic-induced increases in the phosphorylation of neuronal nitric oxide synthase (nNOS) and endothelial NOS in the NTS. These findings suggest that acupuncture at HT7 reduces Nic-induced NE release in the PVN via inhibition of the solitary NMDAR/NOS pathway.
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Terapia por Acupuntura , Nicotina/farmacología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Corticosterona/sangre , Infusiones Intravenosas , Masculino , Microdiálisis , N-Metilaspartato/administración & dosificación , N-Metilaspartato/farmacología , Nicotina/administración & dosificación , Nicotina/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitroprusiato/administración & dosificación , Nitroprusiato/farmacología , Fosforilación/efectos de los fármacos , RatasRESUMEN
Varenicline is a drug used for smoking addiction cessation treatment and acts as a partial agonist of nicotinic cholinergic receptors. Recent clinical trial data support use of varenicline for treatment of conditions/addictions that are not related to smoking cessation. Considering the importance of this issue and the need for new studies on its effects, especially on behavior, more studies using animal models are necessary. Thus, the aim of this study was to evaluate the effects of prolonged exposure to varenicline in anxiety-like behavior and memory, as well as in cerebral neurochemistry of rats. Male rats received three different doses of varenicline: 0.03 (therapeutic dose for humans), 0.1 and 0.3â¯mg/kg orally (gavage) for 30â¯days. Animal behavior was analyzed through open field, elevated plus maze, light/dark box, social interaction, Barnes maze and novel object recognition tests. Neurotransmitter levels and their metabolites in different brain structures (hippocampus, striatum and frontal cortex) were measured. Results showed that prolonged exposure of rats to varenicline: 1) did not interfere in motor activity, but caused an anxiogenic effect on elevated plus maze, light/dark box and social interaction testes; 2) did not alter memory; and 3) promoted alterations on serotoninergic system in the striatum and frontal cortex. In conclusion, compilation of the data indicates that prolonged exposure of rats to varenicline promoted anxiogenic effects and alteration in serotonergic system, which corroborated behavioral findings.
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Ansiedad/inducido químicamente , Memoria/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Neuronas Serotoninérgicas/efectos de los fármacos , Vareniclina/farmacología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Modelos Animales , Actividad Motora/efectos de los fármacos , Nicotina/antagonistas & inhibidores , Agonistas Nicotínicos/administración & dosificación , Ratas , Ratas Wistar , Serotonina/metabolismo , Fumar/tratamiento farmacológico , Cese del Hábito de Fumar/métodos , Vareniclina/administración & dosificación , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction.
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Glicina/análogos & derivados , Nicotina/antagonistas & inhibidores , Ácidos Oléicos/farmacología , Recompensa , Síndrome de Abstinencia a Sustancias/prevención & control , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Condicionamiento Clásico/efectos de los fármacos , Glicina/antagonistas & inhibidores , Glicina/farmacología , Masculino , Mecamilamina/farmacología , Ratones , Nicotina/metabolismo , Nicotina/farmacología , Ácidos Oléicos/antagonistas & inhibidores , Oxazoles/farmacología , PPAR alfa/agonistas , PPAR alfa/antagonistas & inhibidores , Tabaquismo/psicología , Tirosina/análogos & derivados , Tirosina/farmacologíaAsunto(s)
Alcaloides/farmacología , Agonistas Nicotínicos/farmacología , Cese del Hábito de Fumar/métodos , Alcaloides/economía , Alcaloides/uso terapéutico , Azocinas/economía , Azocinas/farmacología , Azocinas/uso terapéutico , Humanos , Metaanálisis como Asunto , Nicotina/antagonistas & inhibidores , Nicotina/farmacología , Agonistas Nicotínicos/economía , Agonistas Nicotínicos/uso terapéutico , Quinolizinas/economía , Quinolizinas/farmacología , Quinolizinas/uso terapéutico , Revisiones Sistemáticas como Asunto , Resultado del TratamientoRESUMEN
We studied the changes in mRNA expressions of influx and efflux transporters, blood-testis-barrier proteins (BTB) and key apoptotic genes in the testis of rats coadministered with nicotine and atorvastatin. Rats were divided into four groups: (i) control, (ii) atorvastatin (10 mg/kg b.wt), (iii) nicotine (0.6 mg/kg b.wt) and (iv) atorvastatin (10 mg/kg b.wt) + nicotine (0.6 mg/kg b.wt). Atorvastatin was given by oral intubation and nicotine by intraperitoneal injection. After 60 days of treatment, expressions of key apoptotic genes involved in both intrinsic and extrinsic pathways; solute carrier influx transporters SLCOB1, SLC22A1 and efflux transporter ABCB1 associated with transport of atorvastatin and nicotine, and proteins of BTB were assayed. Nicotine administration activated apoptosis and downregulated SLCOB1, which transport atorvastatin. Atorvastatin administration suppressed apoptotic pathway and downregulated SLC22A1, transporter of nicotine. Coadministration of atorvastatin with nicotine downregulated expressions of apoptotic genes. The combined administration of atorvastatin and nicotine reduced the influx of both atorvastatin and nicotine and enhanced the efflux of these drugs thereby altering the microenvironment of testis and improving testicular function. We conclude that atorvastatin-mediated alterations of BTB and drug transporters might have played a significant role in ameliorating nicotine-induced testicular toxicity.
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Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Atorvastatina/farmacología , Barrera Hematotesticular , Proteínas de Transporte de Catecolaminas en la Membrana Plasmática/metabolismo , Nicotina/antagonistas & inhibidores , Testículo , Animales , Barrera Hematotesticular/efectos de los fármacos , Barrera Hematotesticular/metabolismo , Masculino , Nicotina/toxicidad , Ratas , Ratas Sprague-Dawley , Proteínas Transportadoras de Solutos/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
Stress seems to be an important risk factor in the beginning and continuing stages of cigarette tobacco smoking in humans. Considering that both of nicotine administration and stress exposure affect cognitive functions including memory formation, the aim of the present study was 1) to evaluate the effect of subcutaneous (s.c.) administration of nicotine on memory formation under stress and 2) to assess the possible role of the basolateral amygdala (BLA) dopamine D1 and D2 receptors in the effect of nicotine on stress-induced memory retrieval impairment. Adult male wistar rats were bilaterally implanted in the BLA. A step-through type passive avoidance task was used to measure memory retrieval. To induce acute stress, the animals were placed on an elevated platform. The results showed that pre-test exposure to 20 and 30â¯min stress, but not 10â¯min, impaired memory retrieval. Nicotine administration (0.05â¯mg/kg, s.c.) improved stress-induced memory retrieval impairment. The activation of the BLA dopamine receptors via bilateral microinjection of apomorphine (0.025-0.4⯵g/rat), a non-selective dopamine receptor agonist, potentiated the effect of nicotine on stress-induced memory retrieval impairment. Interestingly, intra-BLA microinjection of SCH23390 (a selective dopamine D1 receptor antagonist; 0.02-0.5⯵g/rat) or sulpiride (a selective dopamine D2 receptor antagonist; 0.02-0.5⯵g/rat) dose-dependently inhibited nicotine-induced improvement of the stress amnesic effect. Taken together, it can be concluded that stress-induced impairment of memory retrieval can be improved by nicotine administration. Moreover, the dopaminergic neurotransmission in the BLA through D1 and D2 receptors mediates the improving effect of nicotine on stress-induced memory retrieval impairment.
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Complejo Nuclear Basolateral/efectos de los fármacos , Agonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Dopamina/metabolismo , Recuerdo Mental/efectos de los fármacos , Nicotina/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Estrés Psicológico/psicología , Animales , Apomorfina/farmacología , Reacción de Prevención/efectos de los fármacos , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Masculino , Microinyecciones , Nicotina/antagonistas & inhibidores , Ratas , Sulpirida/farmacologíaRESUMEN
A variety of nicotinic drug treatments have been found to decrease nicotine self-administration. However, interactions of drugs affecting different nicotinic receptor subtypes have not been much investigated. This study investigated the interactions between dextromethorphan, which blocks nicotinic α3ß2 receptors as well as a variety of other receptors with sazetidine-A which is a potent and selective α4ß2 nicotinic receptor partial agonist with desensitizing properties. This interaction was compared with dextromethorphan combination treatment with mecamylamine, which is a nonspecific nicotinic channel blocker. Co-administration of dextromethorphan (either 0.5 or 5â¯mg/kg) and lower dose of sazetidine-A (0.3â¯mg/kg) caused a significant reduction in nicotine SA. With regard to food-motivated responding, 3â¯mg/kg of sazetidine-A given alone caused a significant decrease in food intake. However, the lower 0.3â¯mg/kg sazetidine-A dose did not significantly affect food-motivated responding even when given in combination with the higher 5â¯mg/kg dextromethorphan dose which itself caused a significant decrease in food motivated responding. Interestingly, this higher dextromethorphan dose significantly attenuated the decrease in food motivated responding caused by 3â¯mg/kg of sazetidine-A. Locomotor activity was increased by the lower 0.3â¯mg/kg sazetidine-A dose and decreased by the 5â¯mg/kg dextromethorphan dose. Mecamylamine at the doses (0.1 and 1â¯mg/kg) did not affect nicotine SA, but at 1â¯mg/kg significantly decreased food-motivated responding. None of the mecamylamine doses augmented the effect of dextromethorphan in reducing nicotine self-administration. These studies showed that the combination of dextromethorphan and sazetidine-A had mutually potentiating effects, which could provide a better efficacy for promoting smoking cessation, however the strength of the interactions was fairly modest.
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Azetidinas/administración & dosificación , Conducta Adictiva/prevención & control , Conducta Adictiva/psicología , Dextrometorfano/administración & dosificación , Nicotina/administración & dosificación , Nicotina/antagonistas & inhibidores , Piridinas/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Locomoción/efectos de los fármacos , Locomoción/fisiología , Ratas , Ratas Sprague-Dawley , Autoadministración , Agentes para el Cese del Hábito de Fumar/administración & dosificaciónAsunto(s)
Nicotina/antagonistas & inhibidores , Cese del Hábito de Fumar/métodos , Prevención del Hábito de Fumar/métodos , Fumar/tratamiento farmacológico , Femenino , Humanos , Masculino , Nicotina/administración & dosificación , Medición de Riesgo , Dispositivos para Dejar de Fumar Tabaco , Insuficiencia del Tratamiento , Estados UnidosRESUMEN
Colicins are natural non-antibiotic bacterial proteins with a narrow spectrum but an extremely high antibacterial activity. These proteins are promising food additives for the control of major pathogenic Shiga toxin-producing E. coli serovars in meats and produce. In the USA, colicins produced in edible plants such as spinach and leafy beets have already been accepted by the U. S. Food and Drug Administration (FDA) and U. S. Department of Agriculture (USDA) as food-processing antibacterials through the GRAS (generally recognized as safe) regulatory review process. Nicotiana benthamiana, a wild relative of tobacco, N. tabacum, has become the preferred production host plant for manufacturing recombinant proteins-including biopharmaceuticals, vaccines, and biomaterials-but the purification procedures that have been employed thus far are highly complex and costly. We describe a simple and inexpensive purification method based on specific acidic extraction followed by one chromatography step. The method provides for a high recovery yield of purified colicins, as well as a drastic reduction of nicotine to levels that could enable the final products to be used on food. The described purification method allows production of the colicin products at a commercially viable cost of goods and might be broadly applicable to other cost-sensitive proteins.
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Antibacterianos/aislamiento & purificación , Proteínas Bacterianas/aislamiento & purificación , Colicinas/aislamiento & purificación , Aditivos Alimentarios/aislamiento & purificación , Carne/microbiología , Nicotiana/genética , Secuencia de Aminoácidos , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/química , Proteínas Bacterianas/farmacología , Bovinos , Colicinas/biosíntesis , Colicinas/química , Colicinas/farmacología , Aditivos Alimentarios/química , Aditivos Alimentarios/metabolismo , Aditivos Alimentarios/farmacología , Pruebas de Sensibilidad Microbiana , Nicotina/antagonistas & inhibidores , Nicotina/biosíntesis , Plantas Modificadas Genéticamente , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacología , Escherichia coli Shiga-Toxigénica/efectos de los fármacos , Escherichia coli Shiga-Toxigénica/crecimiento & desarrollo , Nicotiana/química , Nicotiana/metabolismoRESUMEN
BACKGROUND: Accumulating evidence suggests that the FDA-approved serotonin 5-HT2C receptor agonist, lorcaserin (Belviq®), may be a promising candidate for the management of substance use disorders, including nicotine addiction. The present study was conducted to determine the efficacy and selectivity of acute or continuous lorcaserin treatment for decreasing the reinforcing effects of nicotine in a primate species. METHODS: Adult rhesus monkeys (n=4) with a history of nicotine self-administration (>2years) responded for injections of nicotine (0.32-100µg/kg IV) or food pellets under a fixed-ratio schedule of reinforcement during daily 100-min sessions. When responding was stable, lorcaserin was administered either as an acute pretreatment (0.1-1.0mg/kg, IM) or by continuous infusion (0.1mg/kg/hr, SC for 3-5days). Daily activity patterns were also monitored immediately following experimental sessions. RESULTS: Results indicate that acute lorcaserin pretreatment produced significant and dose-dependent decreases in nicotine-maintained responding across a >100-fold range of self-administered nicotine doses. Continuous lorcaserin treatment decreased intake of 10µg/kg/inj nicotine to about 50% of baseline values. Food-maintained responding was only moderately decreased in 3 of 4 subjects after acute administration and unaffected in all subjects during continuous treatment. Daily activity also was significantly decreased-to ≤50% of control values-following experimental sessions in which acute lorcaserin was administered. CONCLUSIONS: These data indicate that lorcaserin reduces IV self-administration of nicotine at a dose that decreases motoric activity but less consistently disrupts food-maintained responding. Further research into lorcaserin's potential utility for the management of nicotine dependence is warranted.
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Benzazepinas/farmacología , Nicotina/farmacología , Administración Intravenosa , Animales , Autoantígenos , Benzazepinas/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Alimentos , Infusiones Subcutáneas , Macaca mulatta , Masculino , Actividad Motora/efectos de los fármacos , Nicotina/administración & dosificación , Nicotina/antagonistas & inhibidores , Receptor de Serotonina 5-HT2C , Esquema de Refuerzo , Autoadministración , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificaciónRESUMEN
A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybrid nanoparticle-based nicotine vaccine could be enhanced by modulating hapten localization, providing a promising strategy to combatting nicotine addiction.
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Inmunogenicidad Vacunal , Nicotina/inmunología , Tabaquismo/terapia , Vacunas/inmunología , Análisis de Varianza , Animales , Encéfalo/metabolismo , Proteínas Portadoras/inmunología , Femenino , Haptenos/sangre , Haptenos/inmunología , Haptenos/metabolismo , Ácido Láctico/química , Lípidos/química , Ratones , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Nicotina/antagonistas & inhibidores , Nicotina/sangre , Nicotina/metabolismo , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Balance Th1 - Th2 , Vacunas/administración & dosificación , Vacunas/efectos adversos , Vacunas/farmacocinéticaRESUMEN
RATIONALE: GABAB receptors (GABABR) play a critical role in GABAergic neurotransmission in the brain and are thought to be one of the most promising targets for the treatment of drug addiction. GABABR positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABAB receptor agonists such as baclofen. OBJECTIVES: The present study was aimed at developing novel, selective, and potent GABABR PAMs with efficacy on abuse-related effects of nicotine. RESULTS: We synthetized ~100 analogs of BHF177, a GABABR PAM that has been shown to inhibit nicotine taking and seeking, and tested their activity in multiple cell-based functional assays. Among these compounds, KK-92A displayed superior PAM properties at the GABABR. Interestingly, our results revealed the existence of pathway-selective differential modulation of GABABR signaling by the structurally related GABABR allosteric modulators BHF177 and KK-92A. In vivo, similarly to BHF177, KK-92A inhibited intravenous nicotine self-administration under both fixed- and progressive-ratio schedules of reinforcement in rats. In contrast to BHF177, KK-92A had no effect on food self-administration. Furthermore, KK-92A decreased cue-induced nicotine-seeking behavior without affecting food seeking. CONCLUSIONS: These results indicate that KK-92A is a selective GABABR PAM with efficacy in inhibition of the primary reinforcing and incentive motivational effects of nicotine, and attenuation of nicotine seeking, further confirming that GABABR PAMs may be useful antismoking medications.