RESUMO
Everyday episodic memories involve linking together related events that are temporally separated. However, the mechanisms of forming this temporal association have remained unclear. Here, using astrocyte-specific manipulations, we show that potentiating astrocyte Ca2+ signaling in the hippocampal cornu ammonis 1 (CA1) enhances the strength of such temporal association, in parallel with long-term potentiation (LTP) enhancement of temporoammonic pathway to CA1, whereas attenuation of astrocyte Ca2+ signaling has the opposite effect. Moreover, we identify that these effects are mediated by astrocytic α4 subunit-containing nicotinic acetylcholine receptors (α4-nAChRs) via mechanisms involving NMDAR co-agonist supply. Finally, astrocytic α4-nAChRs underlie the cognitive enhancer nicotine's physiological effects. Together, these findings highlight the importance of astrocyte Ca2+ signaling in cognitive behavior and reveal a mechanism in governing the temporal association of episodic memory formation that operates through α4-nAChRs on hippocampal astrocytes.
Assuntos
Nicotina , Receptores Nicotínicos , Nicotina/farmacologia , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Astrócitos/metabolismo , Hipocampo/metabolismo , Receptores Nicotínicos/metabolismo , Potenciação de Longa Duração/fisiologiaRESUMO
Nicotine is a highly addictive compound present in tobacco, which causes the release of dopamine in different regions of the brain. Recent studies have shown that astrocytes express nicotinic acetylcholine receptors (nAChRs) and mediate calcium signaling. In this study, we examine the morphological and functional adaptations of astrocytes due to nicotine exposure. Utilizing a combination of fluorescence and atomic force microscopy, we show that nicotine-treated astrocytes exhibit time-dependent remodeling in the number and length of both proximal and fine processes. Blocking nAChR activity with an antagonist completely abolishes nicotine's influence on astrocyte morphology indicating that nicotine's action is mediated by these receptors. Functional studies show that 24-hr nicotine treatment induces higher levels of calcium activity in both the cell soma and the processes with a more substantial change observed in the processes. Nicotine does not induce reactive astrocytosis even at high concentrations (10 µM) as determined by cytokine release and glial fibrillary acidic protein expression. We designed tissue clearing experiments to test whether morphological changes occur in vivo using astrocyte specific Aldh1l1-tdTomato knock in mice. We find that nicotine induces a change in the volume of astrocytes in the prefrontal cortex, CA1 of the hippocampus, and the substantia nigra. These results indicate that nicotine directly alters the functional and morphological properties of astrocytes potentially contributing to the underlying mechanism of nicotine abuse.
Assuntos
Nicotina , Receptores Nicotínicos , Animais , Astrócitos/metabolismo , Dopamina/metabolismo , Camundongos , Nicotina/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologiaRESUMO
Nicotine is a highly addictive drug found in tobacco that drives its continued use despite the harmful consequences. The initiation of nicotine abuse involves the mesolimbic dopamine system, which contributes to the rewarding sensory stimuli and associative learning processes in the beginning stages of addiction. Nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs), which come in a diverse collection of subtypes. The nAChRs that contain the α4 and ß2 subunits, often in combination with the α6 subunit, are particularly important for nicotine's ability to increase midbrain dopamine neuron firing rates and phasic burst firing. Chronic nicotine exposure results in numerous neuroadaptations, including the upregulation of particular nAChR subtypes associated with long-term desensitization of the receptors. When nicotine is no longer present, for example during attempts to quit smoking, a withdrawal syndrome develops. The expression of physical withdrawal symptoms depends mainly on the α2, α3, α5, and ß4 nicotinic subunits in the epithalamic habenular complex and its target regions. Thus, nicotine affects diverse neural systems and an array of nAChR subtypes to mediate the overall addiction process. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Assuntos
Encéfalo/metabolismo , Nicotina/metabolismo , Receptores Nicotínicos/metabolismo , Tabagismo/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Humanos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/metabolismo , Subunidades Proteicas/agonistas , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/química , Tabagismo/psicologiaRESUMO
Alcohol use disorder (AUD) causes an alarming economic and health burden in the United States. Unfortunately, this disease does not exist in isolation; AUD is highly comorbid with nicotine use. Results from both human and animal models demonstrate a genetic correlation between alcohol and nicotine behaviors. These data support the idea of shared genetic and neural mechanisms underlying these behaviors. Nicotine acts directly at nicotinic acetylcholine receptors (nAChR) to have its pharmacological effect. Interestingly, alcohol also acts both directly and indirectly at these receptors. Research utilizing genetically engineered rodents and pharmacological manipulations suggest a role for nAChR in several ethanol behaviors. The current manuscript collates this literature and discusses findings that implicate specific nAChR subunits in ethanol phenotypes. These data suggest future directions for targeting nAChR as novel therapeutics for AUD.
Assuntos
Alcoolismo/genética , Alcoolismo/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Tabagismo/genética , Tabagismo/metabolismo , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/tratamento farmacológico , Animais , Etanol/administração & dosagem , Etanol/toxicidade , Humanos , Nicotina/administração & dosagem , Nicotina/metabolismo , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/metabolismo , Tabagismo/tratamento farmacológicoRESUMO
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-ZebraRESUMO
Across species, nicotine can produce robust discriminative stimulus (DS) effects, as with other drugs of abuse, a feature that has been harnessed to advance our understanding on the neuropharmacological mechanisms of nicotine's actions. With the crucial role played by nicotine in supporting tobacco dependence, nicotine DS effects have presented an ideal platform to develop novel generation of smoking cessation compounds. Findings from preclinical strands of research have invigorated the field of human discrimination research to objectively assess nicotine's interoceptive stimulus effects. As such, translation studies provide proof of concept for nicotine DS research as a method to assess the subjective effects of nicotine per se, separate from non-nicotine stimuli involved in smoking. Recent clinical studies with low doses have demonstrated that perceiving nicotine's DS effects is necessary, yet not sufficient, for that dose to be reinforcing. These measures have been instrumental in developing novel strategies with regards to establishing threshold doses of nicotine contained in tobacco products, to then determine subthreshold doses that cannot be discriminated and, therefore, fail to maintain reinforcement. Findings from preclinical and clinical nicotine DS research could substantially inform public health policies aimed at regulating nicotine content of consumer products so that they minimize risks of dependency. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Assuntos
Ensaios Clínicos como Assunto/métodos , Aprendizagem por Discriminação/efeitos dos fármacos , Nicotina/farmacologia , Reforço Psicológico , Animais , Aprendizagem por Discriminação/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Fumar/metabolismo , Fumar/psicologia , Agentes de Cessação do Hábito de Fumar/farmacologia , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Especificidade da Espécie , Tabagismo/tratamento farmacológico , Tabagismo/metabolismo , Tabagismo/psicologiaRESUMO
The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein Gαo1 to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151- knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.
Assuntos
Habenula/fisiologia , Plasticidade Neuronal/fisiologia , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Células CHO , Cricetulus , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Habenula/metabolismo , Humanos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Acoplados a Proteínas G/genética , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologiaRESUMO
Despite health risks associated with smoking, up to 20% of the US population persist in this behavior; many smoke to control body weight or appetite, and fear of post-cessation weight gain can motivate continued smoking. Nicotine and tobacco use is associated with lower body weight, and cessation yields an average weight gain of about 4 kg, which is thought to reflect a return to the body weight of a typical nonsmoker. Nicotine replacement therapies can delay this weight gain but do not prevent it altogether, and the underlying mechanism for how nicotine is able to reduce weight is not fully understood. In rodent models, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Nicotine, acting through nicotinic acetylcholine receptors (nAChRs), increases the firing rate of both orexigenic agouti-related peptide and anorexigenic proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Manipulation of nAChR subunit expression within the ARC can block the ability of nicotine and the nicotinic agonist cytisine from decreasing food intake; however, it is unknown exactly how this reduces food intake. This review summarizes the clinical and preclinical work on nicotine, food intake, and weight gain, then explores the feeding circuitry of the ARC and how it is regulated by nicotine. Finally, we propose a novel hypothesis for how nicotine acts on this hypothalamic circuit to reduce food intake. Implications: This review provides a comprehensive and updated summary of the clinical and preclinical work examining nicotine and food intake, as well as a summary of recent work examining feeding circuits of the hypothalamus. Synthesis of these two topics has led to new understanding of how nAChR signaling regulates food intake circuits in the hypothalamus.
Assuntos
Ingestão de Alimentos/fisiologia , Hipotálamo/metabolismo , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Receptores Nicotínicos/metabolismo , Transdução de Sinais/fisiologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Hipotálamo/efeitos dos fármacos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Abandono do Hábito de Fumar , Fumar Tabaco/metabolismo , Dispositivos para o Abandono do Uso de TabacoRESUMO
Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The α3ß4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the α3ß4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the α3ß4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.
Assuntos
Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/ultraestrutura , Sódio/metabolismo , Microscopia Crioeletrônica , Gânglios Autônomos , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Oligopeptídeos/metabolismo , Técnicas de Patch-Clamp , Estrutura Terciária de ProteínaRESUMO
Electronic cigarette uses propylene glycol and glycerol to deliver nicotine and flavors to the lungs. Given the hundreds of different brands, the thousands of flavors available and the variations in nicotine concentrations, it is likely that electronic cigarette settings and e-liquid composition affect the size distribution of particles emitted and ultimately pulmonary deposition. We used the inExpose e-cigarette extension to study two separate modes of operation of electronic cigarettes, namely power-controlled and the temperature-controlled. We also assessed several e-liquids based on propylene glycol and glycerol concentrations, nicotine content, and selected monomolecular flavoring agents (menthol, vanillin, and maltol). Particle size distribution was measured using a Condensation Particle Counter and a Scanning Mobility Particle Sizer spectrometer. Lung deposition was predicted using the International Commission on Radiological Protection model. For all resistance coils, increase in power delivery generated larger particles while maintaining a higher coil temperature generated smaller particles. Increase in glycerol concentration led to the generation of larger particles. With regard to flavors, we showed that despite minor effect of menthol and maltol, vanillin dramatically increased particle size. Presence of nicotine also increased particle size. Finally, particles emitted by the electronic cigarette were predicted to mainly deposit in the alveoli and conditions generating larger particle sizes led to a reduction in predicted lung deposition. This study shows that coil temperature, propylene glycol and glycerol concentrations, presence of nicotine, and flavors affect the size of particles emitted by an electronic cigarette, directly affecting predicted lung deposition of these particles.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Pulmão/metabolismo , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Temperatura , Vaping , Administração por Inalação , Aerossóis , Desenho de Equipamento , Aromatizantes/administração & dosagem , Aromatizantes/química , Aromatizantes/metabolismo , Glicerol/administração & dosagem , Glicerol/química , Glicerol/metabolismo , Humanos , Modelos Biológicos , Nicotina/química , Nicotina/metabolismo , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Tamanho da Partícula , Propilenoglicol/administração & dosagem , Propilenoglicol/química , Propilenoglicol/metabolismoRESUMO
Nicotine, one of the more than 4700 ingredients in tobacco smoke, is a neurotoxin and once used as pesticides in agriculture. Although its use in agriculture is prohibited in many countries, nicotine intoxication is still a problem among the workers in tobacco farms, and young children as well as adults due to the accidental or suicidal ingestions of nicotine products. Understanding the mechanism of nicotine intoxication is important not only for the prevention and treatment but also for the appropriate regulatory approaches. Here, we review pharmacokinetics of nicotine and the molecular mechanisms for acute and chronic intoxication from nicotine that might be relevant to the central and the peripheral nervous system. We include green tobacco sickness, acute intoxication from popular nicotine products, circadian rhythm changes, chronic intoxication from nicotine through prenatal nicotine exposure, newborn behaviors, and sudden infant death syndrome.
Assuntos
Nicotina/metabolismo , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores Nicotínicos/metabolismo , Tabagismo/metabolismo , Animais , Feminino , Humanos , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/toxicidade , GravidezRESUMO
The disposition and metabolism of nicotine in the brain is an important determinant of its exposure. We have developed a novel method for the dynamic determination of nicotine and its metabolites in rat brain and blood by simultaneous microdialysis sampling, stable-isotope labeling, and ultra high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) assaying. Microdialysis probes were inserted into both the right striatum and jugular vein of Sprague-Dawley rats. The collections of dialystes after nicotine intraperitoneal injection were analyzed by the optimized UHPLC-HRMS. Nicotine-pyridyl- d4 was used as a metabolic tracer, and several stably labeled isotopes were applied to calibrate the in vivo recoveries of retrodialysis. The quadrupole-Orbitrap HRMS provided reliable characterization of the nicotine derivatives with less than 3.5 ppm mass measurement accuracy. Good precision and accuracy were obtained for different analytes within the predefined limits of acceptability and the range of the standard curve. Nicotine and its 11 metabolites were identified in most microdialysis samples from the blood and brain tissue samples. Besides cotinine as the main metabolic product of nicotine, trans-3'-hydroxy-cotinine, nicotine- N-oxide, and norcotinine were proven to be the second most abundant metabolites. The other seven nicotine products, including 4-oxo-4-(3-pyridyl)-butanoic acid, 4-hydroxy-4-(3-pyridyl)-butanoic acid, cotinine- N-oxide, nicotine- N-glucuronide, cotinine- N-glucuronide, and trans-3'- hydroxy-cotinine- O-glucuronide, which have not been determined previously in animal brain, were present in minor amounts. The pharmacokinetic profile of nicotine metabolites indicated that the metabolic characteristic of nicotine in the brain was relatively different from that in the blood. The present work would provide comprehensive evidence for clarifying the differences between nicotine metabolism in the brain and peripheral system.
Assuntos
Nicotina/farmacocinética , Agonistas Nicotínicos/farmacocinética , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Marcação por Isótopo/métodos , Espectrometria de Massas/métodos , Microdiálise/métodos , Nicotina/sangue , Nicotina/metabolismo , Agonistas Nicotínicos/sangue , Agonistas Nicotínicos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The nicotine metabolite ratio (NMR) is a biomarker that represents individual variation in the speed that nicotine is metabolized. The rate of nicotine metabolism alters smoking behavior (eg, amount) and has been validated for personalizing tobacco dependence medication selection to increase treatment efficacy and reduce treatment side effects in the general population of smokers. Although smoking rates are extremely high among those with HIV, the NMR has not been evaluated in this underserved population. METHODS: We used baseline data from a smoking cessation clinical trial for smokers with HIV (N = 131) to examine associations between NMR and demographic, smoking, disease-related, and psychological characteristics. Pearson r and analysis of variance were used to identify univariate correlates of NMR, which were then entered into a multiple linear regression model. RESULTS: In univariate analyses, a higher NMR (faster nicotine metabolism) was associated with being white, and more cigarettes per day, nicotine dependence, exhaled carbon monoxide, and symptoms of depression and anxiety, and using efavirenz. In a multiple regression model, a higher NMR was associated with more cigarettes per day, higher anxiety symptoms, and efavirenz use. CONCLUSIONS: As in other populations, faster nicotine metabolism was associated with the use of more cigarettes and higher anxiety symptoms. Notably, efavirenz use was associated with faster metabolism, which might make it harder to quit smoking for people with HIV treated with that medication. These findings could help guide further study and the clinical use of the NMR to personalize nicotine dependence treatment in this underserved population.
Assuntos
Monóxido de Carbono/metabolismo , Infecções por HIV/metabolismo , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Fumar/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Estudos Transversais , Citocromo P-450 CYP2A6 , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Fumar/epidemiologia , Adulto JovemRESUMO
Parkinson's disease is characterized by progressive death of dopaminergic neurons, leading to motor and cognitive dysfunction. Epidemiological studies consistently show that the use of tobacco reduces the risk of Parkinson's. We report that nicotine reduces the abundance of SIRT6 in neuronal culture and brain tissue. We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine. Additionally, SIRT6 abundance is greater in Parkinson's patient brains, and decreased in the brains of tobacco users. We also identify SNPs that promote SIRT6 expression and simultaneously associate with an increased risk of Parkinson's. Furthermore, brain-specific SIRT6 knockout mice are protected from MPTP-induced Parkinson's, while SIRT6 overexpressing mice develop more severe pathology. Our data suggest that SIRT6 plays a pathogenic and pro-inflammatory role in Parkinson's and that nicotine can provide neuroprotection by accelerating its degradation. Inhibition of SIRT6 may be a promising strategy to ameliorate Parkinson's and neurodegeneration.
Assuntos
Encéfalo/patologia , Regulação da Expressão Gênica/genética , Neurônios/efeitos dos fármacos , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Doença de Parkinson/patologia , Sirtuínas/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Sirtuínas/genéticaRESUMO
Tobacco smoking is particularly evident in individuals experiencing chronic pain. This complex relationship is poorly understood at both molecular and behavioral levels. Here, we describe experiments aimed at understanding whether a chronic pain state induces neuroadaptations into the brain or peripheral nerves that involve nicotinic acetylcholine receptors (nAChRs) and whether these neuroadaptations directly lead to increased vulnerability to nicotine addiction or to the development of coping strategies to relieve pain symptoms. We found that ligation of the rat L5 spinal nerve led to a dramatic downregulation in the mRNA expression levels of all nAChR subunits examined in dorsal root ganglia and a time-dependent downregulation of discrete subunits, particularly in the cingulate cortex and the amygdala. Spinal nerve ligation and sham-operated rats showed minor or no changes in patterns of acquisition and motivation for nicotine taking. Spinal nerve ligation rats also showed similar vulnerability to nicotine seeking as sham animals when reinstatement was induced by nicotine-associated cues, but failed to reinstate lever pressing when relapse was induced by nicotine priming. Spinal nerve ligation and sham rats were equally sensitive to nicotine-induced anxiety-like behavior and antinociception; however, nicotine produced a potent and long-lasting antiallodynic effect in spinal nerve ligation rats. These results demonstrate that chronic pain leads to plasticity of nAChRs that do not directly facilitate nicotine addictive behaviors. Instead, nicotine potently decreases allodynia, an effect that could lead to increased nicotine consumption in chronic pain subjects.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Nicotina/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/metabolismo , Animais , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Modelos Animais de Doenças , Comportamento de Procura de Droga/efeitos dos fármacos , Ligadura , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neuralgia/patologia , Neuralgia/fisiopatologia , Agonistas Nicotínicos/metabolismo , Nociceptividade/efeitos dos fármacos , Medição da Dor , Limiar da Dor/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração , Fatores de TempoRESUMO
Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio. Methods: The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels. Results: During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences. Conclusions: Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Nicotina/metabolismo , Oxazinas/metabolismo , Tabagismo/diagnóstico por imagem , Tabagismo/metabolismo , Adulto , Isótopos de Carbono , Cotinina/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Síndrome de Abstinência a Substâncias/diagnóstico por imagem , Síndrome de Abstinência a Substâncias/metabolismo , Fumar Tabaco/metabolismoRESUMO
Early nicotine exposure is an important cause of further habitual tobacco smoking. Although nicotine has not only rewarding but also aversive properties, the effects of early nicotine exposure on the distinct properties of nicotine are not well known. To reveal the effects of early adolescent nicotine exposure on further persistent tobacco smoking, we demonstrated developmental changes in nicotine-related appetitive and aversive behaviors of rats exposed to nicotine during the late lactation period. Sprague-Dawley rats were injected with saline or nicotine (2, 6 and 12mg/kg). We performed a two bottle free-choice test using escalating doses of nicotine (25, 50 and 100µg/ml), saccharin and quinine and the open field test in both adolescent and adult rats. The rats' aversive response to nicotine was increased according to the increase in nicotine concentration. Adolescent rats showed higher nicotine preference and consumption behaviors than did adult rats at an aversive dose of nicotine. Nicotine-exposed rats increased adolescent nicotine consumption when the nicotine concentration was 12mg/kg. We observed significant increases in anxious behaviors in adolescent nicotine-injected rats compared to saline-injected rats, but there were no alterations in adult rats. In both adolescent and adult rats, saccharin and quinine intake were not significantly different between groups. Taken together, it suggests that repeated nicotine exposure in late lactation period affect changes in aversive nicotine responses and anxious behaviors during adolescence but there is no difference in adults.
Assuntos
Ansiedade/induzido quimicamente , Aprendizagem da Esquiva/efeitos dos fármacos , Lactação/fisiologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Fatores Etários , Análise de Variância , Animais , Peso Corporal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Lactação/efeitos dos fármacos , Masculino , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Quinina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Sacarina/administração & dosagemRESUMO
Introduction: Varenicline doubles cessation over nicotine replacement therapy (NRT) patch for "normal," but not "slow," nicotine metabolizers, as assessed by the nicotine metabolite ratio (NMR). Metabolism-informed care (MIC) could improve outcomes by matching normal metabolizers with non-nicotine medication (e.g., varenicline) and slow metabolizers with NRT patch. Methods: We conducted a feasibility randomized controlled trial of MIC versus guideline based care (GBC) among 81 outpatient adult daily smokers with medical comorbidity. Participants reported perceptions of MIC, underwent blood draw for NMR, and received expert cessation counseling. For MIC participants, medication selection was informed by NMR result (normal (≥0.31) vs. slow (< 0.31)). The primary outcome was MIC feasibility, reflected by attitudes toward MIC and by match rates between NMR and medication. Secondary endpoints (cessation confidence, medication use, smoking status) were assessed over 6 months to inform future studies. Results: Participants were median age 53 years, 46% female, 28% black, and ~90% endorsed MIC. Despite high varenicline prescription rates (~60%) in both arms, NMR-medication matching was higher in MIC (84%) versus GBC (58%) participants (p=0.02); unadjusted odds ratio (OR) 3.67, 95% confidence interval [1.33, 11.00; p-value=0.02]. Secondary endpoints were similar at 1, 3, and 6 months. Conclusions: MIC, an NMR-based precision approach to smoking cessation, was acceptable to 90% of smokers and improved NMR-medication match rates more than 3-fold compared to GBC, even with generally high use of varenicline. These data support the feasibility of MIC, which could maximize efficacy of smoking cessation medication while minimizing side effects and cost. Implications: Among treatment-seeking daily smokers with medical comorbidity, most viewed metabolism-informed care (MIC), guided by the nicotine metabolism ratio (NMR), favorably, and were willing to accept MIC-guided medication. Compared to GBC participants (58%), more MIC participants (84%) were prescribed NMR-matched medication (i.e., normal metabolizers received varenicline; slow metabolizers received NRT patch). MIC increased the odds of optimized matching between NMR and medication more than 3-fold over GBC. Because the number needed to treat (NNT) to help one normal metabolizer quit smoking is only 4.9 for varenicline versus 26 for patch, broad implementation of MIC will improve drug efficacy in normal metabolizers as well as minimize side effects in slow metabolizers.
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Nicotina/metabolismo , Medicina de Precisão/métodos , Agentes de Cessação do Hábito de Fumar/metabolismo , Abandono do Hábito de Fumar/métodos , Fumar Tabaco/metabolismo , Vareniclina/metabolismo , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/efeitos adversos , Nicotina/agonistas , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/uso terapêutico , Projetos Piloto , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Fumar Tabaco/tratamento farmacológico , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/uso terapêuticoRESUMO
INTRODUCTION: While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence. METHODS: In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline. RESULTS: Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels. CONCLUSIONS: These results indicate that 12-week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified.
Assuntos
Adesão à Medicação/estatística & dados numéricos , Agonistas Nicotínicos/uso terapêutico , Abandono do Hábito de Fumar/métodos , Tabagismo/tratamento farmacológico , Vareniclina/uso terapêutico , Adulto , Afeto , Fissura , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nicotina/efeitos adversos , Agonistas Nicotínicos/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Saliva/química , Autorrelato , Síndrome de Abstinência a Substâncias/etiologia , Vareniclina/metabolismoRESUMO
To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of α4ß2-type nicotinic receptors (α4ß2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing α4ß2Rs. Epibatidine itself was trapped; 125I-epibatidine slow release from acidic vesicles was directly measured and required the presence of α4ß2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing α4ß2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in α4ß2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed.