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1.
Neuron ; 109(5): 746-747, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33662269

RESUMO

The circuit that links stress and fear to feeding behavior is poorly understood. In this issue of Neuron, Yang et al. detail a trisynaptic, cannabinoid-dependent circuit that underlies appetite suppression in response to a fearful stimulus and provide evidence of noradrenaline and glutamate co-transmission in locus coeruleus.


Assuntos
Apetite , Locus Cerúleo , Medo , Neurônios , Norepinefrina
2.
Neuropharmacology ; 177: 108256, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738308

RESUMO

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'.

3.
Neuropharmacology ; 177: 108162, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497589

RESUMO

The popularity of e-cigarettes has skyrocketed in recent years, and most vapers use flavored e-cigarette products. Consumption of flavored e-cigarettes exceeds that of combustible cigarettes and other tobacco products among adolescents, who are particularly vulnerable to becoming nicotine dependent. Flavorings have been used by the tobacco industry since the 17th century, but the use of flavors by the e-cigarette industry to create products with "characterizing" flavors (i.e. flavors other than tobacco or menthol) has sparked a public health debate. This review addresses the possibility that characterizing flavors make nicotine more appealing, rewarding and addictive. It also discusses ways in which preclinical and clinical studies could improve our understanding of the mechanisms by which flavors may alter nicotine reward and reinforcement. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

4.
Curr Top Behav Neurosci ; 45: 123-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32451953

RESUMO

Human behavior can be controlled by physical or psychological dependencies associated with addiction. One of the most insidious addictions in our society is the use of tobacco products which contain nicotine. This addiction can be associated with specific receptors in the brain that respond to the natural neurotransmitter acetylcholine. These nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels formed by the assembly of one or multiple types of nAChR receptor subunits. In this paper, we review the structure and diversity of nAChR subunits and our understanding for how different nAChR subtypes play specific roles in the phenomenon of nicotine addiction. We focus on receptors containing ß2 and/or α6 subunits and the special significance of α5-containing receptors. These subtypes all have roles in regulating dopamine-mediated neurotransmission in the mesolimbic reward pathways of the brain. We also discuss the unique roles of homomeric α7 nAChR in behavioral responses to nicotine and how our knowledge of nAChR functional diversity may help guide pharmacotherapeutic approaches for treating nicotine addiction. While nicotine addiction is a truly global problem, the use of areca nut (betel) products is also a serious addiction associated with public health issues across most of South Asia, impacting as many as 600 million people. We discuss how cholinergic receptors of the brain are also involved with areca addiction and the unique challenges for dealing with addiction to this substance.


Assuntos
Comportamento Aditivo , Receptores Nicotínicos , Tabagismo , Humanos , Nicotina , Receptores Colinérgicos
5.
Elife ; 92020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003747

RESUMO

The extensive feedback from the auditory cortex (AC) to the inferior colliculus (IC) supports critical aspects of auditory behavior but has not been extensively characterized. Previous studies demonstrated that activity in IC is altered by focal electrical stimulation and pharmacological inactivation of AC, but these methods lack the ability to selectively manipulate projection neurons. We measured the effects of selective optogenetic modulation of cortico-collicular feedback projections on IC sound responses in mice. Activation of feedback increased spontaneous activity and decreased stimulus selectivity in IC, whereas suppression had no effect. To further understand how microcircuits in AC may control collicular activity, we optogenetically modulated the activity of different cortical neuronal subtypes, specifically parvalbumin-positive (PV) and somatostatin-positive (SST) inhibitory interneurons. We found that modulating the activity of either type of interneuron did not affect IC sound-evoked activity. Combined, our results identify that activation of excitatory projections, but not inhibition-driven changes in cortical activity, affects collicular sound responses.

6.
Nat Commun ; 9(1): 3221, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104567

RESUMO

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.


Assuntos
Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Fatores de Risco , Fumar/efeitos adversos , Adulto Jovem
7.
Neuropharmacology ; 138: 341-348, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29944862

RESUMO

Evidence suggests that there is an association between polymorphisms in the α5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The α5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the role of α5-containing (α5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery of tests in male α5 knockout (KO) mice for a range of ethanol-induced behaviors including hypothermia, hypnosis, and anxiolysis. We also investigated the effects of α5* nAChR on ethanol reward using the Conditioned Place Preference (CPP) assay. Further, we tested the effects of gene deletion on drinking behaviors using the voluntary ethanol consumption in a two-bottle choice assay and Drinking in the Dark (DID, with or without stress) paradigm. We found that deletion of the α5 nAChR subunit enhanced ethanol-induced hypothermia, hypnosis, and an anxiolytic-like response in comparison to wild-type controls. The α5 KO mice showed reduced CPP for ethanol, suggesting that the rewarding properties of ethanol are decreased in mutant mice. Interestingly, Chrna5 gene deletion had no effect on basal ethanol drinking behavior, or ethanol metabolism, but did decrease ethanol intake in the DID paradigm following restraint stress. Taken together, we provide new evidence that α5 nAChRs are involved in some but not all of the behavioral effects of ethanol. Our results highlight the importance of nAChRs as a possible target for the treatment of alcohol dependence.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Receptores Nicotínicos/deficiência , Recompensa , Consumo de Bebidas Alcoólicas/psicologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Depressores do Sistema Nervoso Central/sangue , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Etanol/sangue , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/farmacologia , Hipotermia/induzido quimicamente , Hipotermia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Receptores Nicotínicos/genética , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia
8.
Cancer Res ; 78(12): 3233-3242, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29661830

RESUMO

Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications.Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Retroalimentação Fisiológica , Neoplasias/patologia , Norepinefrina/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Animais , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Neoplasias/mortalidade , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Receptor trkB/metabolismo , Transdução de Sinais , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nicotine Tob Res ; 20(7): 789-799, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29065200

RESUMO

Introduction: Scientific discoveries over the past few decades have provided significant insight into the abuse liability and negative health consequences associated with tobacco and nicotine-containing products. While many of these advances have led to the development of policies and laws that regulate access to and formulations of these products, further research is critical to guide future regulatory efforts, especially as novel nicotine-containing products are introduced and selectively marketed to vulnerable populations. Discussion: In this narrative review, we provide an overview of the scientific findings that have impacted regulatory policy and discuss considerations for further translation of science into policy decisions. We propose that open, bidirectional communication between scientists and policy makers is essential to develop transformative preventive- and intervention-focused policies and programs to reduce appeal, abuse liability, and toxicity of the products. Conclusions: Through these types of interactions, collaborative efforts to inform and modify policy have the potential to significantly decrease the use of tobacco and alternative nicotine products and thus enhance health outcomes for individuals. Implications: This work addresses current topics in the nicotine and tobacco research field to emphasize the importance of basic science research and provide examples of how it can be utilized to inform public policy. In addition to relaying current thoughts on the topic from experts in the field, the article encourages continued efforts and communication between basic scientists and policy officials.


Assuntos
Pesquisa Biomédica/legislação & jurisprudência , Nicotina , Política Pública/legislação & jurisprudência , Produtos do Tabaco/legislação & jurisprudência , Pesquisa Biomédica/métodos , Humanos , Nicotina/normas , Produtos do Tabaco/normas , Tabagismo/prevenção & controle
10.
J Neurochem ; 142 Suppl 2: 130-143, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28791703

RESUMO

Abstinence from chronic use of addictive drugs triggers an aversive withdrawal syndrome that compels relapse and deters abstinence. Many features of this syndrome are common across multiple drugs, involving both affective and physical symptoms. Some of the network signaling underlying withdrawal symptoms overlaps with activity that is associated with aversive mood states, including anxiety and depression. Given these shared features, it is not surprising that a particular circuit, the dorsal diencephalic conduction system, and the medial habenula (MHb) and interpeduncular nucleus (IPN), in particular, have been identified as critical to the emergence of aversive states that arise both as a result and, independently, of drug addiction. As the features of this circuit continue to be characterized, the MHb-IPN axis is emerging as a viable target for therapeutics to aid in the treatment of addiction to multiple drugs of abuse as well as mood-associated disorders. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.


Assuntos
Afeto/efeitos dos fármacos , Ansiedade/tratamento farmacológico , Comportamento Aditivo/tratamento farmacológico , Núcleo Interpeduncular/fisiopatologia , Agonistas Nicotínicos/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Afeto/fisiologia , Animais , Ansiedade/fisiopatologia , Comportamento Aditivo/fisiopatologia , Humanos , Núcleo Interpeduncular/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia
11.
Cell Rep ; 14(8): 1930-9, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26904943

RESUMO

Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP) underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.


Assuntos
Aprendizagem da Esquiva/fisiologia , Região CA1 Hipocampal/fisiologia , Dopamina/metabolismo , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Memória de Longo Prazo/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/farmacologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Eletrodos , Potenciação de Longa Duração/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microtomia , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Sinapses/ultraestrutura , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos
13.
Biochem Pharmacol ; 97(4): 518-530, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26265139

RESUMO

Neuronal nicotinic acetylcholine receptors (nAChRs) containing the α3 subunit are known for their prominent role in normal ganglionic transmission while their involvement in the mechanisms underlying nicotine addiction and smoking-related disease has been emerging only in recent years. The amount of information available on the maturation and trafficking of α3-containing nAChRs is limited. We previously showed that UBXN2A is a p97 adaptor protein that facilitates the maturation and trafficking of α3-containing nAChRs. Further investigation of the mechanisms of UBXN2A actions revealed that the protein interacts with CHIP (carboxyl terminus of Hsc70 interacting protein), whose ubiquitin E3 ligase activity regulates the degradation of several disease-related proteins. We show that CHIP displays E3 ligase activity toward the α3 nAChR subunit and contributes to its ubiquitination and subsequent degradation. UBXN2A interferes with CHIP-mediated ubiquitination of α3 and protects the nicotinic receptor subunit from endoplasmic reticulum associated degradation (ERAD). UBXN2A also cross-talks with VCP/p97 and HSC70/HSP70 proteins in a complex where α3 is likely to be targeted by CHIP. Overall,we identify CHIP as an E3 ligase for α3 and UBXN2A as a protein that may efficiently regulate the stability of CHIP's client substrates.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Receptores Nicotínicos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Retículo Endoplasmático/fisiologia , Degradação Associada com o Retículo Endoplasmático , Complexo de Golgi/fisiologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Células PC12 , Complexo de Endopeptidases do Proteassoma , Ratos , Receptores Nicotínicos/genética , Técnicas do Sistema de Duplo-Híbrido , Ubiquitinação/fisiologia
14.
Neuropsychopharmacology ; 40(10): 2327-36, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25790020

RESUMO

Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.


Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Síndrome de Abstinência a Substâncias/etiologia , Animais , Modelos Animais de Doenças , Feminino , Habenula/efeitos dos fármacos , Habenula/fisiologia , Núcleo Interpeduncular/efeitos dos fármacos , Núcleo Interpeduncular/fisiologia , Masculino , Mecamilamina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Antagonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Fatores de Tempo
15.
Curr Top Behav Neurosci ; 24: 99-123, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25638335

RESUMO

An aversive abstinence syndrome manifests 4-24 h following cessation of chronic use of nicotine-containing products. Symptoms peak on approximately the 3rd day and taper off over the course of the following 3-4 weeks. While the severity of withdrawal symptoms is largely determined by how nicotine is consumed, certain short nucleotide polymorphisms (SNPs) have been shown to predispose individuals to consume larger amounts of nicotine more frequently--as well as to more severe symptoms of withdrawal when trying to quit. Additionally, rodent behavioral models and transgenic mouse models have revealed that specific nicotinic acetylcholine receptor (nAChR) subunits, cellular components, and neuronal circuits are critical to the expression of withdrawal symptoms. Consequently, by continuing to map neuronal circuits and nAChR subpopulations that underlie the nicotine withdrawal syndrome--and by continuing to enumerate genes that predispose carriers to nicotine addiction and exacerbated withdrawal symptoms--it will be possible to pursue personalized therapeutics that more effectively treat nicotine addiction.


Assuntos
Encéfalo , Nicotina/farmacologia , Receptores Nicotínicos/metabolismo , Síndrome de Abstinência a Substâncias , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Humanos , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-25237305

RESUMO

Nicotinic acetylcholine receptors (nAChRs) potently regulate dopamine (DA) release in the striatum and alter cocaine's ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit nAChR-mediated currents in midbrain DA neurons and consequently alter DA release in the dorsal and ventral striatum. At very high concentrations, cocaine also inhibits voltage-gated Na channels in DA neurons. Furthermore, our results show that partial inhibition of nAChRs by cocaine reduces evoked DA release. This diminution of DA release via nAChR inhibition more strongly influences release evoked at low or tonic stimulation frequencies than at higher (phasic) stimulation frequencies, particularly in the dorsolateral striatum. This cocaine-induced shift favoring phasic DA release may contribute to the enhanced saliency and motivational value of cocaine-associated memories and behaviors.

17.
J Neurosci ; 34(12): 4273-84, 2014 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-24647947

RESUMO

The medial habenula (MHb) densely expresses nicotinic acetylcholine receptors (nAChRs) and participates in nicotine-related behaviors such as nicotine withdrawal and regulating nicotine intake. Although specific nAChR subunits are identified as being involved in withdrawal behavior, the cellular mechanisms through which nicotine acts to cause this aversive experience is unclear. Here, we demonstrate an interaction between the nicotinic and neurokinin signaling systems that may form the basis for some symptoms experienced during nicotine withdrawal. Using patch-clamp electrophysiology in mouse brain slices, we show that nicotine (1 µm) increases intrinsic excitability in MHb neurons. This nicotine-induced phenomenon requires α5-containing nAChRs and depends on intact neurokinin signaling. The effect is blocked by preincubation with neurokinin 1 (NK1; L-732138, 10 µm) and NK3 (SB222200, 2 µm) antagonists and mimicked by NK1 (substance P, 100 nm) and NK3 (neurokinin B [NKB], 100 nm) agonists. Microinjections (1 µl) of L-732138 (50 nm) and SB222200 (100 nm) into the MHb induces withdrawal behavior in chronic nicotine-treated (8.4 mg/kg/d, 2 weeks) mice. Conversely, withdrawal behavior is absent with analogous microinjections into the lateral habenula of nicotine-treated mice or in mice chronically treated with a vehicle solution. Further, chronic nicotine reduces nicotine's acute modulation of intrinsic excitability while sparing modulation by NKB. Our work elucidates the interplay between two neuromodulatory signaling systems in the brain through which nicotine acts to influence intrinsic excitability. More importantly, we document a neuroadaptation of this mechanism to chronic nicotine exposure and implicate these mechanisms collectively in the emergence of nicotine withdrawal behavior.


Assuntos
Habenula/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nicotina/farmacologia , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Feminino , Habenula/citologia , Habenula/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurocinina B/farmacologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurônios/citologia , Neurônios/metabolismo , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores Nicotínicos/metabolismo , Substância P/farmacologia , Síndrome de Abstinência a Substâncias/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-23732854

RESUMO

The majority of people who attempt to quit smoking without some assistance relapse within the first couple of weeks, indicating the increased vulnerability during the early withdrawal period. The habenula, which projects via the fasciculus retroflexus to the interpeduncular nucleus, plays an important role in the withdrawal syndrome. Particularly the α2, α5, and ß4 subunits of the nicotinic acetylcholine receptor have critical roles in mediating the somatic manifestations of withdrawal. Furthermore, withdrawal from nicotine induces a hypodopaminergic state, but there is a relative increase in the sensitivity to phasic dopamine release that is caused by nicotine. Therefore, acute nicotine re-exposure causes a phasic DA response that more potently reinforces relapse to smoking during the withdrawal period.


Assuntos
Dopamina/metabolismo , Habenula/metabolismo , Sistema Límbico/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Habenula/efeitos dos fármacos , Humanos , Nicotina/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/efeitos adversos , Receptores Nicotínicos/metabolismo , Reforço Psicológico , Transdução de Sinais , Síndrome de Abstinência a Substâncias/psicologia
19.
Nicotine Tob Res ; 15(5): 983-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23042983

RESUMO

INTRODUCTION: Tobacco addiction has a strong social component. Therefore, nicotinic acetylcholine receptors (nAChR) may influence social behavior. Because the ß4 nicotinic receptor subunit is important for possibly related behaviors, such as anxiety-like behavior and the effects of nicotine, we studied the social behavior of mice null for the ß4 nAChR subunit. METHODS: To measure social behavior, we used the intruder test for social memory in wild-type and littermate ß4 null mice. In addition, we used a nonsocial olfactory memory test as a control. RESULTS: In the intruder test, ß4 null mice showed social amnesia: Wild-type mice spent less time actively interacting with a younger intruder on Day 2 than on Day 1, but ß4 null mice interacted for a similar time on both days. In the nonsocial olfactory memory test, control littermates and ß4 null mice learnt the associations to a similar extent, showing that the amnesic phenotype in the intruder test is specific for social settings. CONCLUSIONS: We conclude that nAChRs that contain the ß4 subunit are important for social behaviors. As those receptors are necessary to observe several effects of nicotine including withdrawal, it is tempting to speculate that the social component of tobacco use is related to the same neuronal circuits responsible for continuing tobacco use in smokers.


Assuntos
Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Comportamento Social , Amnésia , Animais , Ansiedade/genética , Feminino , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Receptores Nicotínicos/metabolismo , Olfato/genética
20.
J Neurochem ; 122(1): 24-37, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22486777

RESUMO

The metabotropic glutamate receptors (mGluRs) fine-tune the efficacy of synaptic transmission. This unique feature makes mGluRs potential targets for the treatment of various CNS disorders. There is ample evidence to show that the ubiquitin proteasome system mediates changes in synaptic strength leading to multiple forms of synaptic plasticity. The present study describes a novel interaction between post-synaptic adaptors, long Homer-3 proteins, and one of the 26S proteasome regulatory subunits, the S8 ATPase, that influences the degradation of the metabotropic glutamate receptor 1α (mGluR1α). We have shown that the two human long Homer-3 proteins specifically interact with human proteasomal S8 ATPase. We identified that mGluR1α and long Homer-3s immunoprecipitate with the 26S proteasome both in vitro and in vivo. We further found that the mGluR1α receptor can be ubiquitinated and degraded by the 26S proteasome and that Homer-3A facilitates this process. Furthermore, the siRNA mediated silencing of Homer-3 led to increased levels of total and plasma membrane-associated mGluR1α receptors. These results suggest that long Homer-3 proteins control the degradation of mGluR1α receptors by shuttling ubiquitinated mGluR-1α receptors to the 26S proteasome via the S8 ATPase which may modulate synaptic transmission.


Assuntos
Proteínas de Transporte/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais/fisiologia , ATPases Associadas a Diversas Atividades Celulares , Animais , Caderinas/metabolismo , Calnexina/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Córtex Cerebral/citologia , Embrião de Mamíferos , Hipocampo/citologia , Proteínas de Arcabouço Homer , Humanos , Neurônios/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/genética , Transfecção , Ubiquitinação/fisiologia
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