RESUMO
BACKGROUND: Modulating the methylation process induces broad biochemical changes, some of which may be involved in schizophrenia. Methylation is in particular central to epigenesis, which is also recognized as a factor in the etiology of schizophrenia. Because methionine administration to patients with schizophrenia has been reported to exacerbate their psychotic symptoms and because mice treated with methionine exhibited social deficits and prepulse inhibition impairment, we investigated whether methionine administration could lead to behavioral changes that reflect schizophrenic symptoms in mice. METHODS: l-Methionine was administered to mice twice a day for 7 days. RESULTS: We found that this treatment induces behavioral responses that reflect the 3 types of schizophrenia-like symptoms (positive, negative, or cognitive deficits) as monitored in a battery of behavioral assays (locomotion, stereotypy, social interaction, forced swimming, prepulse inhibition, novel object recognition, and inhibitory avoidance). Moreover, these responses were differentially reversed by typical haloperidol and atypical clozapine antipsychotics in ways that parallel their effects in schizophrenics. CONCLUSION: We thus propose the l-methionine treatment as an animal model recapitulating several symptoms of schizophrenia. We have established the face and predictive validity for this model. Our model relies on an essential natural amino acid and on an intervention that is relatively simple and time effective and may offer an additional tool for assessing novel antipsychotics.
Assuntos
Modelos Animais de Doenças , Esquizofrenia , Animais , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Clozapina/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Haloperidol/farmacologia , Masculino , Metionina , Camundongos , Atividade Motora/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Filtro Sensorial/efeitos dos fármacos , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Resultado do TratamentoRESUMO
Introduction: Given the rapid increase in teen vaping over recent years it is critical to understand mechanisms underlying addiction and relapse to tobacco use at this age. To evaluate the role of non-nicotine constituents in cigarette smoke, our lab has previously established a model of intravenous self-administration of aqueous cigarette smoke extract (CSE). We now compare the sensitivity of male adolescent and adult rats who have self-administered CSE or nicotine to reinstatement with the pharmacological stressor, yohimbine, with and without cues. Methods: Adolescents and adults, aged postnatal day (P) 34 and 84, were tested for the effect of yohimbine (0-2.5 mg/kg) on plasma corticosterone levels to establish a dose that was an effective stressor at both ages. Separate groups of animals were trained to lever press for food before beginning 1-hour drug self-administration sessions for nicotine or CSE (15 µg/kg/infusion nicotine content). Once stable responding was reached, drug was removed, and behavior extinguished. Drug-seeking behavior was reinstated with yohimbine, cues, or a combination of yohimbine and cues. Results: Although adolescents and adults showed different dose-responses for yohimbine-induced corticosterone release, a dose of 2.5 mg/kg increased stress hormone levels at both ages. Whereas both ages displayed similar responding for CSE and nicotine, adolescents self-administered more CSE and nicotine as compared to adults. Cues and cues + stress reinstated responding to a greater extent in animals that had self-administered CSE, regardless of age. Discussion: These findings suggest that non-nicotine tobacco smoke constituents influence later but not earlier stages of addiction in both adolescent and adult male rats.
RESUMO
The aim of the current study was to determine whether non-nicotine constituents of cigarette smoke contribute to nicotine dependence in adolescent and adult male Sprague Dawley rats. For 10 days animals were given three times daily intravenous injections of nicotine (1.5 mg/kg/day) or cigarette smoke extract (CSE) containing an equivalent dose of nicotine. Both spontaneous and mecamylamine-precipitated withdrawal were then measured. Chronic treatment with CSE induced significantly greater somatic and affective withdrawal signs than nicotine in both adolescents and adults. Mecamylamine-precipitated somatic signs were similar at both ages. In contrast, animals spontaneously withdrawn from chronic drug treatment exhibited significant age differences: whereas adolescents chronically treated with nicotine did not show somatic signs, those treated with CSE showed similar physical withdrawal to those of adults. Mecamylamine did not precipitate anxiety-like behavior at either age. However, both adolescents and adults showed significant anxiety in a light-dark box test 18 h after spontaneous withdrawal. Anxiety-like behavior was still evident in an open field test 1 month after termination of drug treatment, with adolescents showing significantly greater affective symptoms than adults. Our findings indicate that non-nicotine constituents of cigarette smoke do contribute to dependence in both adolescents and adults and emphasize the importance of including smoke constituents with nicotine in animal models of tobacco dependence.
RESUMO
Drug addiction is mediated by complex neuronal processes that converge on the shell of the nucleus accumbens (NAcSh). The NAcSh receives inputs from the lateral hypothalamus (LH), where self-stimulation can be induced. Melanin-concentrating hormone (MCH) is produced mainly in the LH, and its receptor (MCH1R) is highly expressed in the NAcSh. We found that, in the NAcSh, MCH1R is coexpressed with dopamine receptors (D1R and D2R), and that MCH increases spike firing when both D1R and D2R are activated. Also, injecting MCH potentiates cocaine-induced hyperactivity in mice. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference, as well as cocaine sensitization. Using a specific MCH1R antagonist, we further show that acute blockade of the MCH system not only reduces cocaine self-administration, but also attenuates cue- and cocaine-induced reinstatement. Thus, the MCH system has an important modulatory role in cocaine reward and reinforcement by potentiating the dopaminergic system in the NAcSh, which may provide a new rationale for treating cocaine addiction.
Assuntos
Cocaína/farmacologia , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Recompensa , Animais , Comportamento/efeitos dos fármacos , Cocaína/administração & dosagem , Sinais (Psicologia) , Dopamina/metabolismo , Hormônios Hipotalâmicos/administração & dosagem , Hormônios Hipotalâmicos/farmacologia , Masculino , Melaninas/administração & dosagem , Melaninas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Hormônios Hipofisários/administração & dosagem , Hormônios Hipofisários/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Somatostatina/metabolismo , Autoadministração , Estresse Fisiológico/efeitos dos fármacosRESUMO
α5 Subunit-containing GABA(A) receptors (GABA(A)Rs) and α7 neuronal nicotinic-acetylcholine receptors (nAChRs) are members of the Cys-loop family of ligand-gated ion channels (LGICs) that mediate cognitive and attentional processes in the hippocampus. α5 GABA(A)Rs alter network activity by tonic inhibition of CA1/CA3 pyramidal cells of the hippocampus. Postsynaptic α7 nAChRs in the hippocampus regulate inhibitory GABAergic interneuron activity required for synchronization of pyramidal neurons in the CA1, whereas presynaptic α7 nAChRs regulate glutamate release. Can simultaneous allosteric modulation of these LGICs produce synergistic effects on cognition? We show that combined transient application of two allosteric modulators that individually 1) inhibit α5 GABA(A)Rs and 2) enhance α7 nAChRs causes long-term potentiation (LTP) of mossy fiber stimulation-induced excitatory postsynaptic currents (EPSC) from CA1 pyramidal neurons of rat hippocampal slices. The LTP effect evoked by two compounds is replicated by 3-(2,5-difluorophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b]pyridazine (522-054), a compound we designed to simultaneously inhibit α5 GABA(A)Rs and enhance α7 nAChRs. Selective antagonists for either receptor block sustained EPSC potentiation produced by 522-054. In vivo, 522-054 enhances performance in the radial arm maze and facilitates attentional states in the five-choice serial reaction time trial with similar receptor antagonist sensitivity. These observations may translate into therapeutic utility of dual action compounds in diseases of hippocampal-based cognitive impairment.
Assuntos
Cognição/fisiologia , Hipocampo/fisiologia , Canais Iônicos de Abertura Ativada por Ligante/fisiologia , Potenciação de Longa Duração/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Cognição/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de GABA-A/fisiologia , Receptores Nicotínicos/fisiologia , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Although nicotine is generally considered to be the main psychoactive component of tobacco, growing evidence highlights the importance of nonnicotine compounds in smoking reinforcement. Monoamine oxidase (MAO) inhibition is a major consequence of smoking and MAO inhibitors, such as tranylcypromine, increase nicotine reinforcement. Tranylcypromine has multiple pharmacological effects, increasing monoamine release for a few hours immediately after its administration and blocking MAO activity for several days. To assess the relative role of these two actions, adult male rats were tested in consecutive daily 3-h sessions for self-administration of nicotine (3 µg kg⻹) inj⻹, i.v.) either 20 or 1 h following administration of tranylcypromine (3 mg kg⻹). Both paradigms were shown to produce highly significant inhibition of MAO activity. However, whereas animals readily acquired self-administration when pretreated with tranylcypromine 1 h prior to testing, they did not with the longer pretreatment interval. Such animals did immediately acquire nicotine self-administration when the tranylcypromine pretreatment interval was switched to 1 h prior to testing on Day 4, indicating that an acute effect of the MAO inhibitor was responsible for enhanced nicotine reinforcement. Several lines of evidence implicate serotonin (5-HT) as the mediator of this enhancement: (1) Tranyclypromine-enhanced nicotine reinforcement was blocked by the 5-HT2 receptor antagonists, ritanserin and ketanserin; (2) parachloroamphetamine (PCA), a 5-HT releaser, also enhanced nicotine self-administration in animals in which MAO activity was inhibited; (3) pretreatment with tranylcypromine increased PCA-induced 5-HT overflow in the nucleus accumbens. These findings suggest that MAO inhibition enhances serotonergic transmission, which serves a critical role in the reinforcing effects of nicotine.
Assuntos
Serotonina/fisiologia , Tabagismo/metabolismo , Tranilcipromina/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Inibidores da Monoaminoxidase/farmacologia , Ratos , Ratos Sprague-Dawley , Tabagismo/fisiopatologia , Regulação para Cima/fisiologiaRESUMO
GABA(A) receptor (R) positive allosteric modulators that selectively modulate GABA(A)Rs containing beta(2)- and/or beta(3)- over beta(1)-subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"beta(2/3)-selective" GABA(A)R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show alpha-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA(A)R positive allosteric modulators that demonstrate differential beta-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other beta(2/3)-subunit selective, alpha-subunit isoform-selective, BZ and nonBZ GABA(A) positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at beta(1)-subunit-containing GABA(A)Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA(A)R with BZ-like anxiolytic efficacy by reducing or eliminating activity at beta(1)-subunit-containing GABA(A)Rs.
Assuntos
Ansiolíticos/farmacologia , Ataxia/prevenção & controle , Moduladores GABAérgicos/farmacologia , Receptores de GABA-A/fisiologia , Regulação Alostérica , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ataxia/fisiopatologia , Ataxia/psicologia , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacocinética , Humanos , Masculino , Camundongos , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Isoformas de Proteínas/fisiologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Xenopus laevisRESUMO
Heavy smokers display increased radioligand binding of nicotinic acetylcholine receptors (nAChRs). This "upregulation" is thought to be a contributing factor to tobacco dependence. Although cigarette smoke contains thousands of constituents that can contribute to nicotine dependence, it is not well understood whether non-nicotine constituents contribute to nAChR upregulation. In this study, we used an aqueous cigarette smoke extract (CSE), which contains nicotine and soluble constituents of cigarette smoke, to induce nAChR upregulation in adult and adolescent rats. To do this, male rats were exposed to nicotine or CSE (1.5 mg/kg/day nicotine equivalent, intravenously) daily for ten days. This experimental procedure produces equivalent levels of brain and plasma nicotine in nicotine- and CSE-treated animals. We then assessed nAChR upregulation using quantitative autoradiography to measure changes in three nAChR types. Adolescents were found to have consistently greater α4ß2 nAChR binding than adults in many brain regions. Chronic nicotine exposure did not significantly increase nAChR binding in any brain region at either age. Chronic CSE exposure selectively increased α4ß2 nAChR binding in adolescent medial amygdala and α7 binding in adolescent central amygdala and lateral hypothalamus. CSE also increased α3ß4 nAChR binding in the medial habenula and interpeduncular nucleus, and α7 binding in the medial amygdala, independent of age. Overall, this work provides evidence that cigarette smoke constituents influence nAChR upregulation in an age-, nAChR type- and region-dependent manner.
Assuntos
Receptores Nicotínicos/efeitos dos fármacos , Fumaça/efeitos adversos , Envelhecimento , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Autorradiografia , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Nicotina/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Nicotiana , Regulação para Cima/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Despite extensive research, current therapies for smoking cessation are largely ineffective at maintaining abstinence for more than a year. Whereas most preclinical studies use nicotine alone, the goal of the present study was to evaluate whether inclusion of non-nicotine tobacco constituents provides better face validity for the development of new pharmacological therapies for smoking cessation. Here, we trained adult male rats to self-administer nicotine alone or cigarette smoke extract (CSE), which contains nicotine and other aqueous constituents of cigarette smoke. After stable self-administration behavior was established, animals underwent extinction training followed by drug and cue primed reinstatement testing. We show that animals that self-administered CSE had significant reinstatement in all drug and drug + cue stimulus conditions whereas animals that self-administered nicotine only showed significant reinstatement in the drug + cue conditions. AT-1001, an α3ß4 nicotinic acetylcholine receptor (nAChR) functional antagonist, attenuated drug + cue-primed reinstatement of both CSE- and nicotine-seeking behavior. However, AT-1001 was less potent in blocking drug-primed reinstatement in animals that had self-administered CSE than in those that had self-administered nicotine alone. This was the case even when nicotine was used to prime reinstatement in animals that had self-administered CSE, suggesting that prior CSE exposure had altered the functional role of α3ß4-containing nAChRs in drug-seeking behavior. These findings confirm the importance of non-nicotine tobacco constituents and α3ß4* nAChRs in cue- and nicotine-primed craving. They also suggest that tests using CSE may be more valid models to study tobacco dependence than use of nicotine alone.
Assuntos
Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Comportamento de Procura de Droga/efeitos dos fármacos , Nicotiana , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Nicotínicos/efeitos dos fármacos , Fumaça , Animais , Modelos Animais de Doenças , Extinção Psicológica , Masculino , Antagonistas Nicotínicos/farmacologia , Oligopeptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Autoadministração , Abandono do Hábito de Fumar , Produtos do Tabaco , TabagismoRESUMO
Despite persistent public health initiatives, many women continue to smoke during pregnancy. Since maternal smoking has been linked to persisting sex-dependent neurobehavioral deficits in offspring, some consider nicotine to be a safer alternative to tobacco during pregnancy, and the use of electronic nicotine delivery systems is on the rise. We presently show, however, that sustained exposure to low doses of nicotine during fetal development, approximating plasma levels seen clinically with the nicotine patch, produces substantial changes in developing corticostriatal dopamine systems in adolescence. Briefly, pregnant dams were implanted on gestational day 4 with an osmotic minipump that delivered either saline (GS) or nicotine (3 mg/kg/day) (GN) for two weeks. At birth, pups were cross-fostered with treatment naïve dams and were handled daily. Biochemical analyses, signaling assays, and behavioral responses to cocaine were assessed on postnatal day 32, representative of adolescence in the rodent. GN treatment had both sex-dependent and sex-independent effects on prefrontal dopamine systems, altering Catechol-O-methyl transferase (COMT)-dependent dopamine turnover in males and norepinephrine transporter (NET) binding expression in both sexes. GN enhanced cocaine-induced locomotor activity in females, concomitant with GN-induced reductions in striatal dopamine transporter (DAT) binding. GN enhanced ventral striatal D2-like receptor expression and G-protein coupling, while altering the roles of D2 and D3 receptors in cocaine-induced behaviors. These data show that low-dose prenatal nicotine treatment sex-dependently alters corticostriatal dopamine system development, which may underlie clinical deficits seen in adolescents exposed to tobacco or nicotine in utero.
Assuntos
Catecol O-Metiltransferase/metabolismo , Cocaína/farmacologia , Dopamina/metabolismo , Nicotina/farmacologia , Fatores Sexuais , Animais , Animais Recém-Nascidos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Locomoção/efeitos dos fármacos , Masculino , Agonistas Nicotínicos/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologiaRESUMO
Clinical studies have demonstrated an increased incidence of substance misuse and obesity in adolescents whose mothers smoked during pregnancy. Although dopamine systems that mediate natural and drug-induced reinforcement have been shown in animal studies to be altered by gestational nicotine treatment, it is not clear whether there are concomitant changes in reinforcement sensitivity. To test whether prenatal nicotine exposure influences sensitivity to natural and drug rewards, timed pregnant rats were implanted with osmotic minipumps delivering saline or nicotine (3 mg/kg/day) from gestational day 4 to 18. Male offspring were tested as adolescents, on postnatal day 32, for operant responding maintained by sucrose pellets or i.v. cocaine (200 or 500 mug/kg per injection). Cocaine-induced stereotypy and c-fos mRNA expression in cortex and striatum were also examined. Complex changes in reward circuitry were observed in the offspring of nicotine-exposed dams. Nicotine-exposed adolescents did not self-administer the low dose of cocaine, but, at the higher dose, exhibited significantly greater cocaine intake and c-fos mRNA expression in nucleus accumbens than did controls. In contrast, control animals showed significantly greater drug-induced stereotypy at both cocaine doses. Operant responding maintained by sucrose was also influenced by gestational nicotine exposure. At a fixed ratio (FR) 1 schedule, although the number of pellets eaten by the two experimental groups was equivalent, more pellets were left uneaten by nicotine-exposed offspring. At FR2 and FR5 schedules, the responding maintained by sucrose pellets was lower in nicotine-exposed offspring. These findings suggest that nicotine exposure during gestation may induce changes in both natural and drug reward pathways.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Nicotina/farmacologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Reforço Psicológico , Tabagismo/fisiopatologia , Envelhecimento/fisiologia , Animais , Encéfalo/fisiopatologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Causalidade , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Agonistas Nicotínicos/farmacologia , Gravidez , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Fumar/efeitos adversos , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologiaRESUMO
We have previously shown that acetaldehyde, a constituent of tobacco smoke, increases nicotine self-administration in adolescent, but not adult, rats. The aim of this study was to determine whether acetaldehyde influences other behavioral, endocrine, or neuronal responses to nicotine at either age. Juvenile (postnatal day (P) 27) and adult (P90) male Sprague-Dawley rats were treated with saline, acetaldehyde (16 microg/kg/injection x 2, i.v.), nicotine (30 microg/kg/injection x 2, i.v.) or a combination of acetaldehyde and nicotine. Locomotion and center time were evaluated for 30 min in a novel open field, before measurement of plasma corticosterone levels and brain c-fos mRNA. Nicotine increased locomotor activity in juveniles but decreased it in adults; in contrast, center time was increased at both ages. Acetaldehyde potentiated nicotine's locomotor effects, but not center time. Nicotine induced c-fos expression in the bed nucleus of the stria terminalis, the central nucleus of the amygdala (CeA), nucleus accumbens, and the superior colliculus (SC) at both ages, whereas it activated the hypothalamic paraventricular nucleus (PVN) and consequent corticosterone secretion only in adults. Acetaldehyde potentiated nicotine-induced c-fos in CeA and SC, and activation of PVN c-fos expression/plasma corticosterone release; however, this drug interaction was only observed in behaviorally tested animals, not those that were minimally stressed. Thus, acetaldehyde may modulate the interaction of nicotine and stress. Although pharmacokinetic studies showed that acetaldehyde did not change nicotine levels in either brain or serum, nicotine penetration into the brain was slower in juveniles as compared to adults.
Assuntos
Acetaldeído/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Corticosterona/sangue , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hibridização In Situ/métodos , Locomoção/efeitos dos fármacos , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Radioimunoensaio/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Drugs that antagonize nicotinic acetylcholine receptors (nAChRs) can be used to inhibit nicotine-induced behavior in both humans and animals. The aim of our experiments is to establish a proof-of-principle that antagonism of nAChRs by negative allosteric modulation can alter behavior in a relevant animal model of addiction, nicotine self-administration. We have identified a novel, negative allosteric modulator of nAChRs, UCI-30002 [N-(1,2,3,4-tetrahydro-1-naphthyl)-4-nitroaniline], with selectivity for the major neuronal nAChR subtypes over muscle-type nAChRs. After systemic administration, UCI-30002 significantly reduces nicotine self-administration in rats on both fixed ratio and progressive ratio schedules of reinforcement. The minimum effective dose that significantly alters nicotine self-administration corresponds to brain concentrations of UCI-30002 that produce at least 30% inhibition of the major neuronal nAChR subtypes measured in vitro. UCI-30002 has no effect on responding for food reinforcement in rats on either type of schedule, indicating that there is no effect on general responding or natural reward. UCI-30002 represents validation of the concept that negative allosteric modulators may have significant benefits as a strategy for treating nicotine addiction and encourages the development of subtype-selective modulators.
Assuntos
Compostos de Anilina/uso terapêutico , Naftalenos/uso terapêutico , Nicotina/administração & dosagem , Antagonistas Nicotínicos/uso terapêutico , Receptores Nicotínicos/metabolismo , Tabagismo , Sítio Alostérico , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Animais , Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletrofisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/etnologia , Ligantes , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Nicotina/efeitos adversos , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/efeitos adversos , Antagonistas Nicotínicos/farmacocinética , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Autoadministração , Tabagismo/tratamento farmacológico , Tabagismo/metabolismo , Xenopus laevisRESUMO
Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.
Assuntos
Inibidores da Monoaminoxidase/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Tranilcipromina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Envelhecimento/fisiologia , Animais , Benzazepinas/farmacologia , Cromatografia Líquida de Alta Pressão , Cocaína/farmacologia , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Eletroquímica , Meia-Vida , Masculino , Microdiálise , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Recompensa , AutoadministraçãoRESUMO
RATIONALE: Many pregnant women continue to smoke, despite a strong association between maternal smoking and neurobehavioral deficits in the offspring. Although gestational nicotine (GN) treatment in rodents is used as the primary animal model of maternal smoking, tobacco smoke contains more than 4,000 constituents, including monoamine oxidase inhibitors (MAOIs). OBJECTIVES: The aim of this study was to determine whether there are interactions between the effects of gestational exposure to nicotine and MAOIs on cocaine-induced locomotor sensitization in adolescent rats. MATERIALS AND METHODS: Pregnant rats were implanted on day 4 of gestation with osmotic minipumps delivering saline, nicotine (3 mg/kg per day), the MAOIs clorgyline and deprenyl (1 and 0.25 mg/kg per day, respectively), or nicotine/clorgyline/deprenyl (GMN). Adolescent female offspring were tested for cocaine-induced locomotor sensitization. Animals were treated with saline or cocaine (5 or 15 mg/kg, intraperitoneally) daily from postnatal (P) days 32-36 and challenged with cocaine (15 mg/kg) on P51 (day 20). RESULTS: Group differences were observed in chronic but not acute effects of cocaine. Whereas gestational MAOI treatment, with or without nicotine, increased ambulatory response to cocaine on day 5, the opposite was found for vertical activity. Different adaptive responses were observed on cocaine challenge day. GNM animals exhibited enhanced locomotor activity in the cocaine-associated environment before cocaine challenge on day 20. In contrast, only GN animals exhibited significant locomotor sensitization to the cocaine challenge. CONCLUSIONS: Gestational nicotine and MAOIs both influence brain development. Such interactions may sensitize adolescents to drug abuse and should be considered in animal models of maternal smoking.
Assuntos
Cocaína/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Clorgilina/administração & dosagem , Clorgilina/farmacologia , Cocaína/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Análise Fatorial , Feminino , Bombas de Infusão Implantáveis , Injeções Intraperitoneais , Inibidores da Monoaminoxidase/administração & dosagem , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Selegilina/administração & dosagem , Selegilina/farmacologia , Limiar Sensorial/efeitos dos fármacos , Fatores de Tempo , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologiaRESUMO
RATIONALE: The mechanisms mediating tobacco addiction remain elusive. Nicotine, the psychoactive component in tobacco, is generally believed to be the main cause of reward and addiction. However, tobacco smoke contains thousands of constituents, some of which may interact with nicotine to enhance reward. It has previously been shown that monoamine oxidase (MAO) inhibition, known to result from smoking, can enhance nicotine self-administration. The aim of the present study was to evaluate the role of noradrenergic systems in mediating this enhancement of nicotine reward. OBJECTIVE: The objective of this study was to test the hypothesis that MAO inhibitor pretreatment enhances nicotine self-administration by activation of noradrenergic pathways that regulate dopamine release in the nucleus accumbens (NAc). METHODS: The effect of prazosin (0.0625-0.5 mg/kg, i.p.), a specific alpha1-adrenergic receptor antagonist, was examined on male rats pretreated with tranylcypromine (3 mg/kg), an irreversible inhibitor of MAO A and B. Acquisition of nicotine (10 mug kg(-1) inj(-1), i.v.) self-administration behavior was examined over a 5-day period. Nicotine (60 mug kg(-1) inj(-1), i.v.)-induced increase in NAc extracellular dopamine levels was examined by in vivo microdialysis in non-self-administering animals. RESULTS: We have shown that (1) tranylcypromine enhances nicotine self-administration, (2) prazosin pretreatment blocks both the acquisition and the expression of nicotine self-administration, and (3) prazosin pretreatment diminishes nicotine-induced dopamine release in the NAc. CONCLUSION: These data indicate that the stimulation of alpha1-adrenergic receptors is critical for tranylcypromine enhancement of nicotine reward and suggest a critical interplay between the noradrenergic and dopaminergic systems in tobacco addiction.
Assuntos
Inibidores da Monoaminoxidase/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Tranilcipromina/farmacologia , Animais , Comportamento Animal , Cromatografia Líquida de Alta Pressão , Dopamina/metabolismo , Masculino , Microdiálise , Prazosina , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Recompensa , AutoadministraçãoRESUMO
Individuals with attentional and emotional dysfunctions are most at risk for smoking initiation and subsequent nicotine addiction. This article presents converging findings from human behavioral research, brain imaging, and basic neuroscience on smoking as self-medication for attentional and emotional dysfunctions. Nicotine and other tobacco constituents have significant effects on neural circuitry underlying the regulation of attention and affect. Age, sex, early environment, and exposure to other drugs have been identified as important factors that moderate both the effects of nicotine on brain circuitry and behavior and the risk for smoking initiation. Findings also suggest that the effects of smoking differ depending on whether smoking is used to regulate attention or affect. Individual differences in the reinforcement processes underlying tobacco use have implications for the development of tailored smoking cessation programs and prevention strategies that include early treatment of attentional and emotional dysfunctions.
Assuntos
Sintomas Afetivos/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Relações Interpessoais , Fumar/psicologia , Humanos , Nicotina/farmacologia , Abandono do Hábito de FumarRESUMO
Neonatal handling was used to evaluate the influence of early environment on responses to nicotine. Rats exposed as pups to daily short-term separation from the dam (H) were compared to non-handled (NH) controls. In experiment 1, prepubescent males and females, aged postnatal day (P) 30, were tested for the effect of nicotine/acetaldehyde (NicAc) on open field behavior and plasma corticosterone levels. NicAc induced increases in ambulatory activity and time spent in the center of the field in NH, but not H, males. Drug-induced increases in initial ambulatory activity, but not center time, were also seen in NH and H females. Handling, but not sex, contributed to group differences in plasma corticosterone levels. In experiment 2, NH and H rats were tested for acquisition of NicAc self-administration at three ages, P27-31, P34-38 and P90-94. Age and sex, but not handling, contributed to differences in performance of this task. Whereas males exhibited a decrease in responding with age, females did not. These findings demonstrate that neonatal handling may serve as an experimental model for individual differences in sensitivity to tobacco constituents. Furthermore, the current study indicates that stress reactivity, age and sex may play differential roles in initiating smoking behavior.
Assuntos
Acetaldeído/farmacologia , Envelhecimento/fisiologia , Comportamento Animal/efeitos dos fármacos , Glândulas Endócrinas/efeitos dos fármacos , Meio Ambiente , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Animais Recém-Nascidos , Cateterismo Periférico , Corticosterona/sangue , Combinação de Medicamentos , Feminino , Manobra Psicológica , Individualidade , Atividade Motora/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Autoadministração , Caracteres Sexuais , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologiaRESUMO
Adolescence is a critical period for the initiation of drug use, starting with tobacco and alcohol and progressing to marijuana and other illicit drugs. These findings have led to the suggestion that tobacco and alcohol are 'gateway' drugs that sensitize maturing reward pathways to the effects of illicit substances such as cocaine. To test this hypothesis, we have examined whether low-dose nicotine pretreatment alters acquisition of cocaine self-administration in adolescents more than in adults. Male and female Sprague-Dawley rats, aged postnatal day (P) 28 or P86, were given two daily intravenous injections of nicotine (0.03 mg/kg/0.1 ml) or saline for 4 days. At P32 and P90, rats were placed in self-administration chambers and tested for acquisition of cocaine (0.2 or 0.5 mg/kg/inj) for 5 days. Data were collapsed across cocaine dose and sex since there was no significant effect of these variables. Adolescent rats pretreated with nicotine exhibited significantly greater cocaine-reinforced responding as compared to saline controls or adults (p<0.01). This drug pretreatment effect did not generalize to all rewards, since nicotine did not increase responding for sucrose pellets in adolescents. These findings provide evidence that the adolescent brain is uniquely vulnerable to the effects of nicotine on subsequent drug reward.
Assuntos
Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Animais , Animais Recém-Nascidos , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Preferências Alimentares/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
Background: Use of alcohol and tobacco, the two most concurrently abused drugs, typically first occurs during adolescence. Yet, there have been no systematic analyses of ethanol (EtOH) and nicotine (Nic) interactions during adolescence. Recent animal studies report that kappa-opioid (KOR) receptor activation mediates age differences in drug reinforcement. Our hypothesis is that concurrent self-administration of EtOH and Nic will be greater in adolescent rats because of age differences in KOR function. Furthermore, exposure to alcohol and nicotine during adolescence has been reported to increase EtOH intake in adulthood. We performed a longitudinal animal study and hypothesized adolescent rats allowed to self-administer nicotine would drink more alcohol as adults. Methods: Adolescent, postnatal day (P)32, and adult (P90) male and female Sprague-Dawley rats were allowed to self-administer EtOH, Nic, or a combination of both, EtOH+Nic, in an intravenous self-administration paradigm. The role of KOR was pharmacologically evaluated with the KOR antagonist, norbinaltorphamine (norBNI) and with the KOR agonist, U50,488H. Alcohol drinking was subsequently evaluated with male rats in a drinking in the dark (DID), 2-bottle choice test. Results: Concurrent Nic increased EtOH intake in adolescent males, but not in adults or females. Pharmacological blockade of KOR with norBNI robustly increased EtOH+Nic self-administration in adult male rats, but had no effect with female rats. Lastly, in our longitudinal study with male rats, we found prior self-administration of Nic or EtOH+Nic during adolescence increased subsequent oral EtOH intake, whereas prior self-administration of EtOH alone in adults increased subsequent EtOH drinking. Conclusions: There are major age- and sex-differences in the reinforcing effects of EtOH+Nic. Adolescent males are sensitive to the reinforcing interactions of the two drugs, whereas this effect is inhibited by KOR activation in male adults. Nicotine self-administration in adolescent males also increased subsequent oral EtOH intake. These findings suggest that brain mechanisms underlying the reinforcing effects of EtOH and nicotine are both age- and sex-dependent, and that tobacco or e-cigarette use may increase the vulnerability of teenage boys to alcohol abuse.