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1.
Psychopharmacology (Berl) ; 237(9): 2777-2793, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32529265

RESUMO

RATIONALE: Cancer patients receiving the antineoplastic drug paclitaxel report higher incidences and longer duration of treatment-resistant depression than patients receiving other classes of chemotherapeutics. Rodents treated with paclitaxel exhibit a suite of changes in affect-like behaviors. Further, paclitaxel causes chemotherapy-induced peripheral neuropathy (CIPN) in humans and rodents. Kappa opioid receptors (KOR) have a well-established role in depression and neuropathy. The contributions of KOR signaling to paclitaxel-induced aversive-like state and CIPN in rodents remain to be explored. OBJECTIVES: We aimed to investigate whether dysregulation of the KOR/dynorphin system is associated with paclitaxel-mediated pain-like behavior and depression-like behavior. METHODS: Cancer-free male C57BL/6J mice were treated with four injections of vehicle or paclitaxel (32 mg/kg cumulative). The effects of the selective KOR antagonist norbinaltorphimine (norBNI) on paclitaxel-induced sucrose preference deficits and mechanical hypersensitivity were measured. Prodynorphin mRNA and receptor-mediated G protein activation were measured at two time points following the last paclitaxel injection using quantitative real-time polymerase chain reaction and agonist-stimulated [35S]guanosine-5'-O'-(γ-thio)-triphosphate ([35S]GTPγS) binding, respectively, in the nucleus accumbens (NAc), caudate-putamen, amygdala, and spinal cord. RESULTS: Paclitaxel produced a norBNI-reversible sucrose preference deficit, whereas mechanical hypersensitivity was not reversed by norBNI. Paclitaxel treatment increased the levels of mRNA for prodynorphin, a precursor for endogenous KOR agonists, in the NAc. Paclitaxel also had time-dependent effects on KOR-mediated G protein activation in the NAc. CONCLUSIONS: These results suggest that KOR signaling mediates an initial aversive component of paclitaxel, but not necessarily paclitaxel-induced mechanical hypersensitivity.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Aprendizagem da Esquiva/efeitos dos fármacos , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Receptores Opioides kappa/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Aprendizagem da Esquiva/fisiologia , Relação Dose-Resposta a Droga , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo
2.
Psychopharmacology (Berl) ; 236(12): 3593-3599, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31302720

RESUMO

RATIONALE: The α7 nicotinic acetylcholine receptor (nAChR) has been implicated as a target in modulating nicotine reward. However, the effect of pharmacological agents that have been shown to alter the channel properties of the α7 nAChR is not well understood in nicotine reward. OBJECTIVES: This study aimed to investigate the impact of α7 nAChR pharmacological modulation on nicotine conditioned place preference (CPP) in mice by using positive allosteric modulators (PAMs) and a silent agonist. METHODS: The effect of the orthosteric α7 nAChR full agonist PNU282987 (1.3 and 9 mg/kg, s.c.), Type I α7 PAM NS1738 (1 and 10 mg/kg; i.p.), the Type II α7 PAM PNU120596 (0.3, 1, and 3 mg/kg, i.p.), and the α7 silent agonist NS6740 (1 and 3 mg/kg, i.p) on nicotine CPP was measured in mice. Mice were conditioned with either saline or nicotine (0.5 mg/kg) for 3 days in the CPP paradigm. RESULTS: The α7 full orthosteric agonist PNU282987 and the Type II α7 nAChR PAM PNU120596 reduced nicotine CPP, while the silent agonist NS6740 and Type I PAM NS1738 had no effect. The effects of PNU282987 and PNU120596 did not have an effect on morphine CPP. CONCLUSIONS: Taken together, our results suggest that modulation of the α7 nAChR can play important roles in nicotine CPP in mice. In addition, the Type II α7 nAChR PAM PNU120596 attenuated nicotine reward suggesting that endogenous acetylcholine/choline tone is sufficient to reduce nicotine CPP. These findings highlight a beneficial effect of using α7 nAChR PAMs in nicotine reward.


Assuntos
Condicionamento Clássico/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR
3.
Eur J Pain ; 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29633429

RESUMO

BACKGROUND: Preclinical assays of affective and sensorial aspects of nociception play a key role in research on both the neurobiology of pain and the development of novel analgesics. Therefore, we investigated the effects of nicotine and alpha-7 nicotinic acetylcholine receptor (nAChR) modulators in the negative affective and sensory components of visceral pain in mice. METHODS AND RESULTS: Intraperitoneal acetic acid (AA) administration resulted in a robust stretching behaviour and conditioned place aversion (CPA) in mice. We observed a dose-dependent reduction in AA-induced stretching and CPA by the nonselective nAChRs agonist nicotine. Mecamylamine, a nonselective nAChRs agonist, was able to block its effects; however, hexamethonium, a peripherally restricted nonselective nicotinic antagonist, was able to block nicotine's effect on stretching behaviour but not on CPA. In addition, systemic administration of α7 nAChR full agonists PHA543613 and PNU282987 was failed to block stretching and CPA behaviour induced by AA. However, the α7 nAChR-positive allosteric modulator PNU120596 blocked AA-induced CPA in a dose-dependent manner without reducing stretching behaviours. CONCLUSIONS: Our data revealed that while nonselective nAChR activation induces antinociceptive properties on the sensorial and affective signs of visceral pain in mice, α7 nAChRS activation has no effect on these responses. In addition, nonselective nAChR activation-induced antinociceptive effect on stretching behaviour was mediated by central and peripheral mechanisms. However, the effect of nonselective nAChR activation on CPA was mediated centrally. Furthermore, our data suggest a pivotal role of allosteric modulation of α7 nAChRS in the negative affective, but not sensory, component of visceral pain. SIGNIFICANCE: The present results suggest that allosteric modulation of α7 nAChR may provide new strategies in affective aspects of nociception.

4.
Eur J Pain ; 22(1): 84-93, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28809075

RESUMO

BACKGROUND: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The α4ß2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of α4ß2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for α4ß2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at α4ß2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. METHODS: The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response. RESULTS: We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the α4ß2 nAChRs by using competitive α4ß2 antagonist dihydro-ß-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to α4ß2 nAChRs. CONCLUSIONS: The present results suggest that allosteric modulation of α4ß2 nAChR may provide new strategies in chronic neuropathic pain. SIGNIFICANCE: α4ß2 nAChRs are involved in pain modulation. dFBr, a PAM at α4ß2 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of α4ß2* nAChR may provide new strategies in chronic neuropathic pain.


Assuntos
Hidrocarbonetos Bromados/uso terapêutico , Alcaloides Indólicos/uso terapêutico , Neuralgia/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hidrocarbonetos Bromados/farmacologia , Alcaloides Indólicos/farmacologia , Masculino , Camundongos , Neuralgia/metabolismo , Nicotina , Agonistas Nicotínicos/farmacologia
5.
Br J Pharmacol ; 173(10): 1678-92, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26915789

RESUMO

BACKGROUND AND PURPOSE: Inhibition of diacylglycerol lipase (DGL)ß prevents LPS-induced pro-inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGLß inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models. EXPERIMENTAL APPROACH: Initial experiments examined the cellular expression of DGLß and inflammatory mediators within the LPS-injected paw pad. DAGL-ß (-/-) mice or wild-type mice treated with the DGLß inhibitor KT109 were assessed in the LPS model of inflammatory pain. Additional studies examined the locus of action for KT109-induced antinociception, its efficacy in chronic constrictive injury (CCI) of sciatic nerve and chemotherapy-induced neuropathic pain (CINP) models. KEY RESULTS: Intraplantar LPS evoked mechanical allodynia that was associated with increased expression of DGLß, which was co-localized with increased TNF-α and prostaglandins in paws. DAGL-ß (-/-) mice or KT109-treated wild-type mice displayed reductions in LPS-induced allodynia. Repeated KT109 administration prevented the expression of LPS-induced allodynia, without evidence of tolerance. Intraplantar injection of KT109 into the LPS-treated paw, but not the contralateral paw, reversed the allodynic responses. However, i.c.v. or i.t. administration of KT109 did not alter LPS-induced allodynia. Finally, KT109 also reversed allodynia in the CCI and CINP models and lacked discernible side effects (e.g. gross motor deficits, anxiogenic behaviour or gastric ulcers). CONCLUSIONS AND IMPLICATIONS: These findings suggest that local inhibition of DGLß at the site of inflammation represents a novel avenue to treat pathological pain, with no apparent untoward side effects.


Assuntos
Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Lipase Lipoproteica/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Lipase Lipoproteica/deficiência , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/metabolismo , Relação Estrutura-Atividade
6.
Psychopharmacology (Berl) ; 233(6): 995-1003, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26676982

RESUMO

RATIONALE: N-acetylcysteine can increase extrasynaptic glutamate and reduce nicotine self-administration in rats and smoking rates in humans. OBJECTIVES: The aim of this study was to determine if N-acetylcysteine modulates the development of nicotine place conditioning and withdrawal in mice. METHODS: N-acetylcysteine was given to nicotine-treated male ICR mice. Experiment 1: reward-like behavior. N-acetylcysteine (0, 5, 15, 30, or 60 mg/kg, i.p.) was given 15 min before nicotine (0.5 mg/kg, s.c.) or saline (10 ml/kg, s.c.) in an unbiased conditioned place preference (CPP) paradigm. Conditioning for highly palatable food served as control. Experiment 2: spontaneous withdrawal. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured 18-24 h after continuous nicotine (24 mg/kg/day, 14 days). Experiment 3: mecamylamine-precipitated, withdrawal-induced aversion. The effect of N-acetylcysteine (0, 15, 30, 120 mg/kg, i.p.) on mecamylamine (3.5 mg/kg, i.p.)-precipitated withdrawal was determined after continuous nicotine (24 mg/kg, i.p., 28 days) using the conditioned place aversion (CPA) paradigm. RESULTS: Dose-related reductions in the development of nicotine CPP, somatic withdrawal signs, hyperalgesia, and CPA were observed after N-acetylcysteine pretreatment. No effect of N-acetylcysteine was found on palatable food CPP, anxiety-like behavior, or motoric capacity (crosses between plus maze arms). Finally, N-acetylcysteine did not affect any measure in saline-treated mice at doses effective in nicotine-treated mice. CONCLUSIONS: These are the first data suggesting that N-acetylcysteine blocks specific mouse behaviors associated with nicotine reward and withdrawal, which adds to the growing appreciation that N-acetylcysteine may have high clinical utility in combating nicotine dependence.


Assuntos
Acetilcisteína/farmacologia , Aprendizagem por Associação/efeitos dos fármacos , Nicotina/efeitos adversos , Recompensa , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Acetilcisteína/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Masculino , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Tabagismo/tratamento farmacológico
7.
Psychopharmacology (Berl) ; 232(15): 2763-71, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25761841

RESUMO

BACKGROUND: Preclinical studies with bupropion in rodent models of nicotine dependence have generated equivocal findings with regard to translating the clinical efficacy of the antidepressant as a smoking cessation agent. OBJECTIVE: Given that rats are poor metabolizers of bupropion, the present experiments examined (2S,3S)-hydroxybupropion, the major active metabolite, on the positive reinforcing and aversive stimulus properties of nicotine in rats. METHODS: In male hooded Lister rats, (2S,3S)-hydroxybupropion (1.0-10.0 mg/kg IP) was tested on intravenous nicotine (0.03 mg/kg/inf) self-administration behaviour for three sessions (n = 8), and in another experiment, the same doses of (2S,3S)-hydroxybupropion were tested in a conditioned taste aversion procedure to assess the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake. RESULTS: (2S,3S)-hydroxybupropion attenuated nicotine intake in a manner similar to that produced by mecamylamine pretreatment (1.0 mg/kg SC). This effect on nicotine-taking was specific since these doses had no effect on responding maintained by sucrose presented orally (200 µl of 5 % w/v). (2S,3S)-hydroxybupropion (1, 3 and 10 mg/kg IP) pretreatment failed to modify the aversive effects produced by a small dose of nicotine (0.1 mg/kg SC). CONCLUSIONS: These results demonstrate this metabolite to specifically modify the positive reinforcing effects of nicotine without affecting its aversive motivational effects. We propose that the clinical efficacy of bupropion may be due to a combination of effects produced by bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine and noradrenaline in reward centres of the brain and the noncompetitive antagonism of neuronal nicotinic receptors.


Assuntos
Bupropiona/análogos & derivados , Nicotina/administração & dosagem , Receptores Nicotínicos/fisiologia , Recompensa , Abandono do Hábito de Fumar , Animais , Antidepressivos/uso terapêutico , Aprendizagem da Esquiva/efeitos dos fármacos , Bupropiona/farmacologia , Masculino , Ratos , Autoadministração , Tabagismo
8.
Neuropharmacology ; 96(Pt B): 223-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25433149

RESUMO

Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.


Assuntos
Encéfalo/fisiopatologia , Neurônios/fisiologia , Receptores Nicotínicos/fisiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Tabagismo/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Tabagismo/genética , Tabagismo/metabolismo
9.
Br J Pharmacol ; 172(3): 869-82, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25258021

RESUMO

BACKGROUND AND PURPOSE: Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored. EXPERIMENTAL APPROACH: To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets. KEY RESULTS: BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB1 receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans. CONCLUSIONS AND IMPLICATIONS: Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.


Assuntos
Benzodioxóis/farmacologia , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Nicotina/antagonistas & inibidores , Piperidinas/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Monoacilglicerol Lipases/deficiência , Monoacilglicerol Lipases/metabolismo , Nicotina/administração & dosagem , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Br J Pharmacol ; 171(16): 3845-57, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24750073

RESUMO

BACKGROUND AND PURPOSE: Recent data have indicated that α3ß4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. EXPERIMENTAL APPROACHES: To assess the role of α3ß4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. KEY RESULTS: BXD recombinant mouse lines demonstrated an increased expression of α3, ß4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and ß4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3ß4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4ß2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. CONCLUSION AND IMPLICATIONS: Overall, our findings suggest an important role for the α3ß4* nACh receptor subtype in morphine physical dependence.


Assuntos
Dependência de Morfina/genética , Receptores Nicotínicos/genética , Animais , Humanos , Masculino , Mesencéfalo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Prosencéfalo/metabolismo , RNA Mensageiro/metabolismo , Receptores Nicotínicos/metabolismo
11.
Genes Brain Behav ; 13(2): 213-25, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24289814

RESUMO

Mortality from tobacco smoking remains the leading cause of preventable death in the world, yet current cessation therapies are only modestly successful, suggesting new molecular targets are needed. Genetic analysis of gene expression and behavior identified Chrna7 as potentially modulating nicotine place conditioning in the BXD panel of inbred mice. We used gene targeting and pharmacological tools to confirm the role of Chrna7 in nicotine conditioned place preference (CPP). To identify molecular events downstream of Chrna7 that may modulate nicotine preference, we performed microarray analysis of α7 knock-out (KO) and wild-type (WT) nucleus accumbens (NAc) tissue, followed by confirmation with quantitative polymerase chain reaction (PCR) and immunoblotting. In the BXD panel, we found a putative cis expression quantitative trait loci (eQTL) for Chrna7 in NAc that correlated inversely to nicotine CPP. We observed that gain-of-function α7 mice did not display nicotine preference at any dose tested, whereas conversely, α7 KO mice demonstrated nicotine place preference at a dose below that routinely required to produce preference. In B6 mice, the α7 nicotinic acetylcholine receptor (nAChR)-selective agonist, PHA-543613, dose-dependently blocked nicotine CPP, which was restored using the α7 nAChR-selective antagonist, methyllycaconitine citrate (MLA). Our genomic studies implicated a messenger RNA (mRNA) co-expression network regulated by Chrna7 in NAc. Mice lacking Chrna7 demonstrate increased insulin signaling in the NAc, which may modulate nicotine place preference. Our studies provide novel targets for future work on development of more effective therapeutic approaches to counteract the rewarding properties of nicotine for smoking cessation.


Assuntos
Variação Genética , Nicotina/farmacologia , Fenótipo , Recompensa , Receptor Nicotínico de Acetilcolina alfa7/genética , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Condicionamento Clássico , Redes Reguladoras de Genes , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Locos de Características Quantitativas , Quinuclidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
12.
Neurosci Lett ; 550: 129-33, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23810802

RESUMO

Smoking rates among individuals with schizophrenia are significantly higher than the general population. One possible explanation for this comorbidity is that there are shared genes and biological pathways between smoking and schizophrenia. The histidine triad nucleotide binding protein 1 (HINT1) is a potential candidate, as genetic association and expression studies implicate the gene in both schizophrenia and nicotine dependence; however, the behavioral role of HINT1 in nicotine dependence is unknown. Thus, the goal of the current study was to determine the behavioral role of HINT1 in nicotine dependence. We tested male HINT1 wild-type (+/+) and knockout (-/-) mice in the nicotine conditioned place preference (CPP) test of reward, a nicotine withdrawal model assessing both physical and affective signs, and the nicotine withdrawal conditioned place aversion (CPA) test. HINT1 -/- mice failed to develop a significant nicotine CPP and physical withdrawal signs (hyperalgesia and somatic signs) were attenuated in HINT1 -/- mice. Conversely, HINT1 -/- mice developed a significant nicotine withdrawal CPA similar to their ++ counterparts. Overall, our data support a role for the HINT1 gene in mediating behaviors associated with nicotine reward and physical nicotine withdrawal, and provide insight into the role of HINT1 in nicotine dependence-like behaviors.


Assuntos
Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Nicotina/efeitos adversos , Recompensa , Síndrome de Abstinência a Substâncias/metabolismo , Tabagismo/metabolismo , Animais , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Síndrome de Abstinência a Substâncias/genética , Tabagismo/genética
13.
Psychopharmacology (Berl) ; 228(3): 419-26, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23503685

RESUMO

RATIONALE: Several studies suggest that repeated nicotine administration causes alterations in glutaminergic transmission that may play an important role in developing and maintaining nicotine addiction. Chronic nicotine administration in rats decreases the expression of the glutamate transporter-1 (GLT-1) and cysteine-glutamate exchanger (system xC-) in the nucleus accumbens. We hypothesized that ceftriaxone, a GLT-1 and system xC- activator, would decrease murine behavioral aspects of nicotine dependence. OBJECTIVE: This study aimed to investigate the effect of repeated ceftriaxone administration on the behavioral effects of nicotine using mouse models of conditioned reward and withdrawal. METHOD: Using male ICR mice, the ability of repeated ceftriaxone injections to modulate the development and reinstatement of a nicotine-conditioned place preference (CPP) was evaluated. Additionally, nicotine withdrawal-associated signs were assessed. These included both physical (somatic signs and hyperalgesia) and affective (anxiety-related behaviors) withdrawal signs in mice. Finally, the effects of ceftriaxone on nicotine-induced antinociception and hypothermia after acute nicotine injection were measured. RESULT: Ceftriaxone had no effect on the development of nicotine preference but significantly attenuated nicotine-induced reinstatement of CPP. Furthermore, ceftriaxone reversed all nicotine withdrawal signs measured in mice. CONCLUSION: Altogether, these findings show that a ß-lactam antibiotic reduces nicotine withdrawal and nicotine-seeking behavior. Our results suggest that the documented efficacy of ceftriaxone against cocaine and morphine dependence-related behaviors effects extends to nicotine.


Assuntos
Antibacterianos/farmacologia , Ceftriaxona/farmacologia , Nicotina/efeitos adversos , Reforço Psicológico , Síndrome de Abstinência a Substâncias/prevenção & controle , Tabagismo/psicologia , Sistemas de Transporte de Aminoácidos/agonistas , Sistemas de Transporte de Aminoácidos/antagonistas & inibidores , Animais , Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Condicionamento Psicológico/efeitos dos fármacos , Cisteína/metabolismo , Transportador 2 de Aminoácido Excitatório/agonistas , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Extinção Psicológica , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Recompensa , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Tabagismo/metabolismo
14.
Br J Pharmacol ; 169(3): 567-79, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23004024

RESUMO

BACKGROUND AND PURPOSE: The α7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that α7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the α7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II α7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model. EXPERIMENTAL APPROACH: We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective α7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice. KEY RESULTS: We found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and α7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of α7 nAChRs. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that type II α7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous α7 agonist choline.


Assuntos
Analgésicos/uso terapêutico , Modelos Animais de Doenças , Isoxazóis/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Dor Nociceptiva/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Dor Aguda/tratamento farmacológico , Regulação Alostérica , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Colina/administração & dosagem , Colina/efeitos adversos , Colina/uso terapêutico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Nicotina/efeitos adversos , Nicotina/uso terapêutico , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Medição da Dor , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Quinuclidinas/efeitos adversos , Quinuclidinas/uso terapêutico , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
15.
Psychopharmacology (Berl) ; 226(4): 763-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22526543

RESUMO

RATIONALE: Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference. OBJECTIVES: In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference. METHODS: Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session. RESULTS: Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine-primed reinstatement. CONCLUSIONS: Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general.


Assuntos
Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Nicotina/administração & dosagem , Estresse Psicológico/psicologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Extinção Psicológica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Recidiva , Fatores de Risco , Autoadministração , Fumar/epidemiologia
16.
Genes Brain Behav ; 11(8): 993-1000, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22827509

RESUMO

Human genetic association and brain expression studies, and mouse behavioral and molecular studies implicate a role for the histidine triad nucleotide-binding protein 1 (HINT1) in schizophrenia, bipolar disorder, depression and anxiety. The high comorbidity between smoking and psychiatric disorders, schizophrenia in particular, is well established. Associations with schizophrenia and HINT1 are also sex specific, with effects more predominant in males; however, it is unknown if sex differences associated with the gene extend to other phenotypes. Thus, in this study, using a battery of behavioral tests, we elucidated the role of HINT1 in acute nicotine-mediated behaviors using male and female HINT1 wild-type (+/+) and knockout (-/-) mice. The results show that male HINT1 -/- mice were less sensitive to acute nicotine-induced antinociception in the tail-flick, but not hot-plate test. At low nicotine doses, male and female HINT1 -/- mice were less sensitive to nicotine-induced hypomotility, although the effect was more pronounced in females. Baseline differences in locomotor activity observed in male HINT1 +/+ and -/- mice were absent in females. Nicotine did not produce an anxiolytic effect in male HINT1 -/- mice, but rather an anxiogenic response. Diazepam also failed to induce an anxiolytic response in these mice, suggesting a general anxiety phenotype not specific to nicotine. Differences in anxiety-like behavior were not observed in female mice. These results further support a role for HINT1 in nicotine-mediated behaviors and suggest that alterations in the gene may have differential effects on phenotype in males and females.


Assuntos
Comportamento Animal/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Nicotina/farmacologia , Animais , Ansiedade/genética , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Knockout , Nociceptividade/efeitos dos fármacos , Fenótipo , Fatores Sexuais
17.
Psychopharmacology (Berl) ; 223(2): 159-68, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22526534

RESUMO

RATIONALE: Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4ß2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment. OBJECTIVES: The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4ß2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration. METHODS: Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day). RESULTS: 4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration. CONCLUSIONS: These results support the hypothesis that neuronal α4ß2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4ß2 nAChRs may yield a potential candidate for the treatment of nicotine dependence.


Assuntos
Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Nicotina/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/metabolismo , Recompensa , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/química , Condicionamento Operante/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/química , Piridinas/administração & dosagem , Piridinas/química , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Wistar , Autoadministração , Autoestimulação/efeitos dos fármacos , Especificidade da Espécie
18.
J Pharmacol Exp Ther ; 334(1): 137-46, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20400469

RESUMO

Incorporation of the alpha5 nicotinic acetylcholine receptor (nAChR) subunit can greatly influence nAChR function without altering receptor number. Although few animal studies have assessed the role of the alpha5 nAChR in nicotine-mediated behaviors, recent evidence suggests an association between polymorphisms in the alpha5 nAChR gene and nicotine dependence phenotypes in humans. Thus, additional studies are imperative to elucidate the role and function of the alpha5 nAChR subunit in nicotine dependence. Using alpha5(-/-) mice, the current study aimed to examine the role of alpha5 nAChRs in the initial pharmacological effects of nicotine, nicotine reward using the conditioned place preference model, and the discriminative effects of nicotine using a two-lever drug discrimination model. (86)Rb(+) efflux and (125)I-epibatidine binding assays were conducted to examine the effect of alpha5 nAChR subunit deletion on expression and activity of functional nAChRs. Results show that alpha5(-/-) mice are less sensitive to the initial effects of nicotine in antinociception, locomotor activity, and hypothermia measures and that the alpha5 nAChR is involved in nicotine reward. Alternatively, alpha5(-/-) mice did not differ from wild-type littermates in sensitivity to the discriminative stimulus effects of nicotine. Furthermore, deletion of the alpha5 nAChR subunit resulted in a statistically significant decrease in function in the thalamus and hindbrain, but the decreases noted in spinal cord were not statistically significant. Receptor number was unaltered in all areas tested. Taken together, results of the study suggest that alpha5 nAChRs are involved in nicotine-mediated behaviors relevant to development of nicotine dependence.


Assuntos
Comportamento Animal/efeitos dos fármacos , Nicotina/farmacologia , Receptores Nicotínicos/fisiologia , Analgésicos Opioides/farmacologia , Animais , Temperatura Corporal , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Hipotermia/induzido quimicamente , Hipotermia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Dor/metabolismo , Limiar da Dor/efeitos dos fármacos , Ligação Proteica , Receptores Nicotínicos/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
19.
Psychopharmacology (Berl) ; 210(2): 285-94, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20232057

RESUMO

RATIONALE: Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking. OBJECTIVE: The objective of this study is to determine the involvement of the KOR in the initial behavioral responses of nicotine, nicotine reward, and nicotine withdrawal using the highly selective KOR antagonist JDTic. JDTic doses of 1, 4, 8, or 16 mg/kg were administered subcutaneously (s.c.) 18 h prior to nicotine treatment. RESULTS: JDTic dose-dependently blocked acute nicotine-induced antinociception in the tail-flick but not the hot-plate test and did not significantly attenuate morphine's antinociceptive effect in either the tail-flick or hot-plate test. Furthermore, JDTic (8 and 16 mg/kg, s.c.) failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic and the KOR antagonist norBNI attenuated the expression of both the physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and conditioned place aversion) nicotine withdrawal signs. CONCLUSIONS: Our findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence. The results from this study suggest that blockade of the KOR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.


Assuntos
Analgésicos/farmacologia , Nicotina/farmacologia , Piperidinas/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Recompensa , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Analgésicos/efeitos adversos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Buprenorfina/análogos & derivados , Buprenorfina/farmacologia , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Hipotermia/induzido quimicamente , Masculino , Camundongos , Morfina/farmacologia , Nicotina/efeitos adversos , Síndrome de Abstinência a Substâncias/psicologia
20.
J Pharmacol Exp Ther ; 331(2): 547-54, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19644040

RESUMO

The alpha6 nicotinic acetylcholine receptor (nAChR) subunit is involved in nicotine-stimulated dopamine release in the striatum. It is expressed in brain regions and coexpressed with nAChR subtypes implicated in nicotine dependence behaviors; hence, this subunit may play a role in nicotine dependence. Using the alpha6-selective antagonist alpha-conotoxin H9A;L15A (MII[H9A;L15A]), we determined the role of alpha6* nAChRs in the pharmacological and behavioral effects of nicotine. We measured effects of pretreatment with MII[H9A;L15A] on analgesia, locomotion, and body temperature after a single injection of nicotine. Effects of MII[H9A;L15A] on nicotine reward were measured using the conditioned place preference (CPP) paradigm. We further measured physical (somatic signs and hyperalgesia) and affective [anxiety-related behavior and conditioned place aversion (CPA)] nicotine withdrawal behaviors after extended nicotine exposure. Results showed that MII[H9A;L15A] did not block acute nicotine effects on the behaviors measured. Conversely, MII[H9A:l15A] blocked the expression of nicotine CPP, as well as withdrawal-associated CPA and anxiety-related behavior in the elevated plus maze, but not withdrawal-induced somatic signs or hyperalgesia. These results suggest a role for the alpha6 nAChR subunit in nicotine reward and affective nicotine withdrawal but not acute nicotine-induced or physical withdrawal behaviors.


Assuntos
Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Recompensa , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Ansiedade/psicologia , Aprendizagem da Esquiva/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Condicionamento Operante/efeitos dos fármacos , Conotoxinas/farmacologia , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Antagonistas Nicotínicos/farmacologia , Medição da Dor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/psicologia
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