RESUMO
The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.
Assuntos
Alcoolismo/genética , Globo Pálido/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Adulto , Consumo de Bebidas Alcoólicas , Alcoolismo/tratamento farmacológico , Alcoolismo/fisiopatologia , Alelos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Depressores do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Etanol/administração & dosagem , Feminino , Neuroimagem Funcional , Estudos de Associação Genética , Genótipo , Humanos , Imageamento por Ressonância Magnética , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Testes Neuropsicológicos , Peptídeos/farmacologia , Autoadministração , Adulto JovemRESUMO
Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Grelina/farmacologia , Receptores Nicotínicos/fisiologia , Transdução de Sinais/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Análise de Variância , Animais , Colina O-Acetiltransferase/metabolismo , Condicionamento Operante/efeitos dos fármacos , Vias de Administração de Medicamentos , Interações Medicamentosas , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Preferências Alimentares/efeitos dos fármacos , Preferências Alimentares/fisiologia , Hexametônio/farmacologia , Masculino , Mecamilamina/farmacologia , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Antagonistas Nicotínicos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/deficiência , Receptores Nicotínicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Área Tegmentar Ventral/citologiaRESUMO
The revised practice guideline 'Otitis media with effusion' from the Dutch College of General Practitioners constitutes a valuable contribution to the discussion regarding the diagnosis and treatment of this condition. A few critical comments can, however, be made. Pneumatic otoscopy and physical examination are considered to be very valuable. However, many general practitioners do not possess either the means or the skill to perform these investigations correctly. Patients with signs of (serious) hearing impairment should in the first place be referred to an otorhinolaryngologist, who can then refer children with proven perceptive hearing loss to a centre for audiology. This practice guideline recommends referral to an otorhinolaryngologist in case of hearing loss of more than 30 dB; according to otorhinolaryngologists this should be 25 dB or more. However, the duration and severity of the symptoms are more important. Speech and language retardation, behavioural problems at school due to hearing impairment and the possible development of an atelectatic tympanum are important reasons for referral. Otorhinolaryngologists also object to the wait-and-see attitude that is recommended in the practice guideline. Since there is no unambiguous evidence regarding the consequences ofotitis media with effusion in the long term, it would seem more reasonable to take the decision whether or not to treat the condition (and if so, when) in consultation with the parents. It is the parents who can best judge whether the child can live with the negative consequences of an untreated otitis media with effusion.
Assuntos
Otite Média com Derrame/diagnóstico , Otite Média com Derrame/terapia , Otolaringologia/normas , Médicos de Família/normas , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Humanos , Países Baixos , Otoscopia/métodos , Exame Físico , Encaminhamento e ConsultaRESUMO
RATIONALE: Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like syndromes can be induced in humans by phencyclidine (PCP), a drug with marked psychomimetic properties. Recent studies show that the behavioural and biochemical effects of PCP in rats are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in the pharmacological effects of PCP. OBJECTIVE: The aim of this study was to investigate if PCP-induced disruption of prepulse inhibition of acoustic startle could be blocked by the NOS inhibitor, L-NAME, in mice. RESULTS: The present study shows that PCP readily disrupts prepulse inhibition in mice normally without affecting pulse-alone trials. Furthermore, L-NAME blocked the PCP-induced disruption of prepulse inhibition in a dose-related manner. CONCLUSIONS: The PCP-induced disruption of prepulse inhibition and the ability of L-NAME to block this effect in both rats and mice suggest that this is a general and not a species-specific effect. The results of the present study further suggest that PCP exerts at least some of its actions in the central nervous system by a NO-dependent mechanism.
Assuntos
Inibidores Enzimáticos/farmacologia , Alucinógenos/antagonistas & inibidores , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Fenciclidina/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica , Animais , Relação Dose-Resposta a Droga , Alucinógenos/farmacologia , Masculino , Camundongos , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Fenciclidina/farmacologiaRESUMO
RATIONALE: Repeated exposure to addictive drugs causes neuroadaptive alterations that are proposed to increase the incentive motivation to consume drugs and to decrease the ability to inhibit such inappropriate motivational impulses and responses. Together, these behavioral consequences of drug intake may underlie the compulsive drug-seeking and -taking behaviors observed in drug abuse. OBJECTIVE: Brain serotonin (5-HT) has been implicated in these mechanisms and this study therefore investigated the consequences of brain 5-HT depletion on the behavioral and neurochemical effects induced by repeated daily nicotine treatment (15 days) in male rats. METHODS: The effects of the present pharmacological manipulations were evaluated behaviorally (locomotor activity, the elevated plus-maze) and neurochemically (microdialysis, brain biochemistry). RESULTS: Depletion of brain 5-HT produced behavioral disinhibition in the elevated plus-maze. In 5-HT-depleted animals, nicotine-induced locomotor sensitization was observed on treatment days 5, 10, and 15, but only on day 15 in the sham-operated rats. Postsensitization, the locomotor stimulatory effects of amphetamine and the dopamine receptor agonists SKF 38,393, apomorphine, and quinpirole were decreased in 5-HT-depleted animals, an effect that appeared to be more pronounced in nicotine-treated rats. Repeated nicotine treatment sensitized the nicotine-induced elevation of the extracellular accumbal dopamine levels in sham-operated, but not in 5-HT-depleted rats, and was also associated with decreased D2 autoreceptor function in both nicotine-treated experimental groups. CONCLUSIONS: Depletion of brain 5-HT, which produces behavioral disinhibition, may slightly facilitate the overall expression of locomotor sensitization to nicotine and differentially affect the pre- and postsynaptic neuroadaptive events involved in the expression of these phenomena.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Serotonina/fisiologia , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Ansiedade/psicologia , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Serotoninérgicos/farmacologiaRESUMO
This study investigated the effects of repeated daily (15 days) treatment with nicotine, alone or in combination with the 5-HT1A/7 receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or the 5-HT2 receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) on locomotor sensitization, mesolimbic dopamine neurochemistry and on behavioral inhibition in the rat. Acute nicotine elevated the extracellular dopamine levels in the nucleus accumbens and stimulated locomotor activity, effects that were sensitized after repeated nicotine treatment. Repeated nicotine administration also produced nicotine-induced behavioral disinhibition in the elevated plus-maze. Treatment with DOI counteracted the expression of the nicotine-induced locomotor and neurochemical sensitization, but had no effect on nicotine-induced behavioral disinhibition. Treatment with 8-OH-DPAT decreased the expression of nicotine-induced behavioral disinhibition, but had no effect on locomotor or neurochemical sensitization. Taken together, these findings suggest that the 5-HT1A and the 5-HT2 receptor subtypes are differentially involved in the effects of repeated nicotine on locomotor sensitization, behavioral inhibition and mesolimbic dopamine neurochemistry.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anfetaminas/farmacologia , Comportamento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Animais , Encéfalo/metabolismo , Dopamina/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microdiálise , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Fatores de TempoRESUMO
This article represents the proceedings of a symposium at the ISBRA Meeting in Yokohama, Japan. The chairs were A. D. Lê and K. Kiianmaa. The presentations were (1) Alcohol reward and aversion, by C. L. Cunningham; (2) The role of sensitization of neuronal mechanisms in ethanol self-administration, by J. A. Engel, M. Ericson, and B. Söderpalm; (3) Alcohol self-administration in dependent animals: Neurobiological mechanisms, by G. F. Koob, A. J. Roberts, and F. Weiss; (4) Stress and relapse to alcohol, by A. D. Lê; (5) Alcohol-preferring AA and alcohol-avoiding ANA rats differ in locomotor activation induced by repeated morphine injections, by P. Hyytiä, S. Janhunen, J. Mikkola, P. Bäckström, and K. Kiianmaa; and (6) Initial sensitivity and acute functional tolerance to the hypnotic effects of ethanol in mice genetically selected for mild and severe ethanol withdrawal convulsions, by I. Ponomarev and J. C. Crabbe.
Assuntos
Alcoolismo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Etanol/farmacologia , Recompensa , Alcoolismo/genética , Animais , Condicionamento Psicológico/fisiologia , Tolerância a Medicamentos , Humanos , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Fenótipo , Ratos , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de GABA/efeitos dos fármacos , Receptores de GABA/metabolismo , Reforço Psicológico , Autoadministração , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Bo Söderpalm. The presentations were (1) Nicotinic mechanisms and ethanol reinforcement: Behavioral and neurochemical studies, by Bo Söderpalm, M. Ericson, P. Olausson, and J. A. Engel; (2) Chronic nicotine and ethanol: Differential regulation in gene expression of nicotinic acetylcholine receptor subunits, by X. Zhang and A. Nordberg; (3) Nicotine-ethanol interactions at neuronal nicotinic acetylcholine receptors, by Toshio Narahashi, William Marszalec, and Gary L. Aistrup; (4) Relapse prevention in alcoholics by cigarette smoking? Treatment outcome in an observational study with acamprosate, by L.G. Schmidt, U. Kalouti, M. Smolka, and M. Soyka; and (5) Effect of nicotine on voluntary ethanol intake and development of alcohol dependence in male rats, by L. Hedlund and G. Wahlström.
Assuntos
Alcoolismo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Expressão Gênica/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Fumar/metabolismo , Acamprosato , Acetilcolina/farmacologia , Dissuasores de Álcool/farmacologia , Alcoolismo/tratamento farmacológico , Animais , Interações Medicamentosas/fisiologia , Humanos , Masculino , Nicotina/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Ratos , Receptores Nicotínicos/metabolismo , Reforço Psicológico , Prevenção Secundária , Taurina/análogos & derivados , Taurina/farmacologia , Vasodilatadores/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
This study investigated the effects of repeated daily nicotine (0.35 mg/kg; 15 days) treatment on behavioral inhibition and locomotor activity in the elevated plus-maze and on voluntary ethanol consumption. When challenged with nicotine before the test, rats pretreated with repeated nicotine spent more time on and made more entries onto the open arms of an elevated plus-maze than did vehicle-pretreated animals. The ethanol preference and intake, measured during 3 h after a nicotine injection, was also higher in the nicotine-pretreated animals. In ethanol consumption experiments, there was a positive correlation between the % time and % entries made onto open arms vs. the ethanol preference and intake. However, no correlation between the total number of entries made in the elevated plus-maze and the measures of ethanol consumption was observed. These findings suggest that the ability of repeated nicotine administration to increase ethanol consumption is related to development of a nicotine-induced reduction of inhibitory control rather than development of locomotor sensitization.
Assuntos
Comportamento Animal/efeitos dos fármacos , Etanol/farmacologia , Nicotina/farmacologia , Análise de Variância , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
It is a well-known fact that a large percentage of alcoholics smoke, and in the experimental rat, intermittent nicotine administration enhances ethanol intake and ethanol preference in a free-choice situation between 6% (v/v) ethanol and water. The present study focuses on the possible involvement of central and/or peripheral nicotine acetylcholine receptors (nAChR) in nicotine-induced sensitization to dopamine-related behavioral effects of ethanol. Wistar rats drinking less than 60% of their total daily fluid from a 6% ethanol solution were used in the study. Nicotine, vehicle, mecamylamine, hexamethonium, mecamylamine+nicotine, and hexamethonium+nicotine were administered subchronically for 15 days. All groups, except the vehicle pre-treated group, markedly increased their ethanol preference to approximately 80%, as well as their ethanol intake. NMRI mice received the same treatments for 10 days, after which ethanol (2.5 g/kg, intraperitoneal (i.p.)) was given acutely and locomotor activity was recorded. Ethanol-induced locomotor stimulation was enhanced in most groups, as compared to the vehicle pre-treated group. Administration of quarternary autonomic drugs to ethanol high-preferring rats (hexamethonium, methscopolamine, sotalol and phentolamine) according to different acute and chronic treatment protocols indicated that the enhanced ethanol intake may involve increased ganglionic and/or peripheral muscarinic neurotransmission. Taken together, the above results indicate that peripheral mechanisms may be involved in the enhancement of dopamine-related behavioral effects of ethanol observed after subchronic intermittent treatment with nicotinic drugs.
Assuntos
Consumo de Bebidas Alcoólicas , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Ingestão de Líquidos/efeitos dos fármacos , Masculino , Camundongos , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Wistar , Receptores Nicotínicos/fisiologiaRESUMO
Ethanol shares with all major dependence producing drugs the ability to activate brain mesocorticolimbic dopamine neurons, an important part of the brain reward systems. This dopamine activation may be involved in mediating the positive reinforcing effects of ethanol. The mechanisms of action of ethanol in its activation of this dopamine system remain, however, to be elucidated. A selective pharmacological interference with these mechanisms may offer a possibility to reduce the reinforcing properties of ethanol without simultaneously interfering with the reinforcing properties of natural rewards. Ethanol has been shown to directly influence the function of various ligand-gated ion-channels. Several of these are located on or nearby mesocorticolimbic dopamine neurons. One such receptor is the nicotinic acetylcholine receptor (nAChR). The present article reviews a series of investigations aimed at investigating whether nAChRs are involved in the dopamine activating and reinforcing properties of ethanol. To this end acute and chronic behavioral and neurochemical experiments were performed in mice and rats. The results obtained indicate that central nAChRs in the ventral tegmental area are involved in mediating the mesolimbic dopamine activating and reinforcing effects of ethanol. Furthermore, the ethanol-induced activation of these receptors is probably indirect, subsequent to a primary interference of ethanol in the nucleus accumbens. Moreover, subchronic nicotine treatment enhances the reinforcing and dopamine activating properties of ethanol. This long-term effect may, however, derive from autonomic adaptations in response to intermittent blockade of peripheral nAChRs (rather than from intermittent stimulation of central receptors), and appears to be associated with development of a disinhibitory behavior that could involve also other neurotransmitters, e.g. serotonin. Taken together, these findings could provide a neurobiological explanation to the often observed co-abuse of nicotine and ethanol in man. Furthermore, since the behavioral models applied previously have predicted therapeutic drug effects in the clinic, the results suggest that selective blockade of the ventral tegmental nAChRs that are involved in the above effects may provide a new pharmacological alternative in the treatment of alcoholism.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Encéfalo/fisiopatologia , Dopamina/fisiologia , Motivação , Receptores Nicotínicos/fisiologia , Animais , Mapeamento Encefálico , Humanos , Camundongos , Ratos , Tabagismo/fisiopatologiaRESUMO
This study investigated the effects of repeated amphetamine treatment on locomotor activity and behavioral inhibition in the elevated plus-maze, and the influence of serotonin (5-HT) neurotransmission on these behaviors. Acute administration of amphetamine (1.0 mg/kg subcutaneously [SC]) stimulated locomotor activity, which was attenuated by acute citalopram (5.0 mg/kg SC) pretreatment. Repeated daily treatment with amphetamine (15 days) sensitized the rats to the amphetamine-induced locomotor stimulation. Acute pretreatment with the 5-HT precursor l-5-hydroxytryptophan (5-HTP; 25 mg/kg IP) or chronic treatment with the selective 5-HT reuptake inhibitor citalopram (5.0 mg/kg SC, twice daily), did not alter the expression of amphetamine-induced locomotor sensitization. In the elevated plus-maze, animals subjected to repeated amphetamine treatment expressed behavioral disinhibition after amphetamine exposure (1.0 mg/kg SC; -35 min), which was antagonized both by acute 5-HTP and chronic citalopram treatment. In summary, these findings suggest that behavioral sensitization to amphetamine is associated with amphetamine-induced behavioral disinhibition, and that acute 5-HTP as well as chronic citalopram treatment counteract the expression of amphetamine-induced behavioral disinhibition, but not locomotor sensitization. It appears likely that the antagonistic effects of 5-HTP and citalopram on behavioral disinhibition derive from a drug-induced facilitation of brain 5-HT neurotransmission.
Assuntos
Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Serotonina/fisiologia , 5-Hidroxitriptofano/farmacologia , Animais , Citalopram/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The present study investigated the effects of subchronic nicotine, mecamylamine and hexamethonium, alone or in combinations, on locomotor activity and behavioral inhibition. Rats were divided into groups and tested for locomotor activity after acute nicotine. The different groups received vehicle, nicotine, mecamylamine, mecamylamine+nicotine, hexamethonium (two different concentrations) and hexamethonium+nicotine injections once a day for 15 days after which they were tested for nicotine-induced locomotor activity again. Acutely, nicotine stimulated locomotor activity, and repeated daily nicotine or hexamethonium+nicotine administration sensitized the animals to this nicotine-induced locomotor stimulation (locomotor sensitization). Mecamylamine administered subchronically in combination with nicotine was able to block the induction to locomotor sensitization to nicotine. None of the nicotinic receptor antagonists induced locomotor sensitization to nicotine by themselves. In the elevated plus-maze, subchronic nicotine treatment demonstrated a nicotine-induced behavioral disinhibition, measured as an increase of time spent in and entries made into open arms. In contrast to the findings regarding locomotor sensitization, none of the antagonists counteracted the induction of this nicotine-induced behavioral disinhibition after subchronic co-treatment with nicotine. In addition, both antagonists by themselves produced a similar effect as subchronic nicotine, i.e. promoted the development of nicotine-induced disinhibitory behavior. It was concluded that the induction of locomotor sensitization to nicotine involves stimulation of central nicotinic acetylcholine receptors, whereas the development of nicotine-induced behavioral disinhibition involves blockade of peripheral nicotinic acetylcholine receptors, and that the latter, but not the former, phenomenon from a pharmacological point of view appears to be related to the increased ethanol consummatory behavior observed after subchronic nicotine administration.
Assuntos
Comportamento Animal/efeitos dos fármacos , Nicotina/farmacologia , Sistema Nervoso Periférico/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Animais , Hexametônio/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Mecamilamina/farmacologia , Atividade Motora/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Sistema Nervoso Periférico/fisiologia , Ratos , Ratos WistarRESUMO
RATIONALE: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. OBJECTIVE: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. RESULTS: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. CONCLUSIONS: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.
Assuntos
Dopamina/fisiologia , Reflexo de Sobressalto/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Estimulação Acústica , Anfetamina/farmacologia , Análise de Variância , Animais , Cocaína/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Masculino , Ruído , Quimpirol/farmacologia , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
The effects of gonadectomy on shock-induced behavioral inhibition in a modified Vogel's drinking conflict model and on diazepam-induced disinhibition and sedation were investigated in adult male rats. Gonadectomy enhanced shock-induced behavioral inhibition when determined 9, 21, 45, and 65 days, but not 3 days, after operation, without affecting shock sensitivity or drinking motivation. Testosterone-substitution for 21 days following gonadectomy prevented this enhanced inhibition without significantly affecting the behavior in sham-operated rats. Diazepam produced behavioral disinhibition both in sham-operated and gonadectomized rats. However, after the highest dose (16 mg/kg, IP) the disinhibited behavior decreased only in sham-operated animals, most likely due to sedation. Moreover, whereas there was no difference in basal rotarod-performance between controls and gonadectomized rats, the latter animals were less sensitive to diazepam-induced disruption of rotarod walking ability. Sham-operated or gonadectomized animals did not differ with respect to serum diazepam levels at the postinjection times used in the behavioral tests. Taken together, gonadectomized rats were less sensitive towards diazepam-induced sedation, possibly due to a subsensitivity at or beyond GABA(A)/benzodiazepine receptors. Furthermore, the finding that lack of testosterone enhanced shock-induced inhibition could be interpreted to reflect increased impulse control and may involve an altered activation of GABA(A)/benzodiazepine receptors.
Assuntos
Condicionamento Operante/fisiologia , Comportamento Impulsivo/psicologia , Orquiectomia , Animais , Ansiolíticos/farmacologia , Diazepam/farmacocinética , Diazepam/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento de Ingestão de Líquido/fisiologia , Eletrochoque , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Masculino , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Testosterona/farmacologia , Privação de Água/fisiologiaRESUMO
The effect of neonatal brain infection of herpes simplex virus type 1 (HSV-1) on the development of sensorimotor function in the rat was investigated using an acoustic startle paradigm. Intracerebral inoculation of HSV-1 at day 2 after birth, but not at day 4, caused a significant delay in the development of prepulse inhibition of acoustic startle. A decrease in prepulse inhibition was shown at 37, 46 and 58 days of age in these rats compared to control rats. No evidence was obtained for other behavioural dysfunctions such as differences in sensorimotor reactivity, sensorimotor response habituation, spontaneous locomotor activity, rearing activity or stereotyped behaviour. Prepulse inhibition of acoustic startle is an accepted model of sensorimotor gating in the CNS, a function which has been shown diminished in schizophrenic persons. The present results suggest that early viral infections during a neurone-susceptible period may contribute to the development of this deficit.
Assuntos
Encéfalo/fisiopatologia , Encéfalo/virologia , Encefalite por Herpes Simples/fisiopatologia , Herpesvirus Humano 1/fisiologia , Desempenho Psicomotor/fisiologia , Esquizofrenia/fisiopatologia , Esquizofrenia/virologia , Fatores Etários , Animais , Animais Recém-Nascidos , Peso Corporal/fisiologia , Encéfalo/patologia , DNA Viral/análise , DNA Viral/metabolismo , Modelos Animais de Doenças , Encefalite por Herpes Simples/patologia , Feminino , Atividade Motora/fisiologia , Inibição Neural/fisiologia , Neuroglia/patologia , Neuroglia/virologia , Neurônios/patologia , Neurônios/virologia , Reação em Cadeia da Polimerase , Gravidez , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/fisiologia , Esquizofrenia/patologia , Taxa de Sobrevida , Fatores de Tempo , Carga ViralRESUMO
Impulsive and aggressive behaviors in, e.g., personality or substance abuse disorders in man and corresponding behaviors in rats may involve serotonin (5-HT), gamma-amino-butyric acid(A)/benzodiazepine receptor complexes (GABA(A)/BDZ-RC) and steroid hormones, e.g., testosterone. Here, we studied the effect of gonadectomy on disinhibitory behavior in individually housed 5-HT-depleted rats and on GABA(A)/BDZ-RC function in vitro, in corticohippocampal synaptoneurosomes prepared from the brain of these animals. 5-HT depletion by intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT)-induced disinhibitory behavior in a shock-induced behavioral inhibition model (punished conflict model) 14 days after operation. Gonadectomy in connection with the 5-HT depletion reduced the disinhibitory behavior and testosterone substitution prevented this effect. Shock threshold and drinking motivation were not affected by gonadectomy and/or 5-HT depletion. The relative epididymides weight was increased in 5-HT-depleted as compared to sham-operated rats. However, the serum concentrations of testosterone and the relative testes weights were not different in 5-HT-depleted rats as compared to controls. GABA-induced (30, 100, 300 microM) 36Cl(-)-uptake into synaptoneurosomes was lower in 5,7-DHT+gonadectomized rats compared to the control group. This effect was reversed by substitution with testosterone. These results demonstrate that gonadectomy reduces disinhibitory behavior in 5-HT-depleted rats and that GABA(A)/BDZ-RC may be involved in this effect.
Assuntos
Comportamento Animal/fisiologia , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Inibição Psicológica , Orquiectomia , Receptores de GABA-A/metabolismo , Serotonina/metabolismo , 5,7-Di-Hidroxitriptamina , Animais , Masculino , Ratos , Ratos Sprague-Dawley , SerotoninérgicosRESUMO
Recent clinical and experimental data indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. In the present study we have investigated whether bovine GH (bGH) transgenic mice and nontransgenic controls differ in spontaneous locomotor activity, a behavioral response related to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity response to drugs of abuse known to interfere with brain DA systems. The animals were tested for locomotor activity once a week for 4 weeks. When first exposed to the test apparatus, bGH transgenic animals displayed significantly more locomotor activity than controls during the entire registration period (1 h). One week later, after acute pretreatment with saline, the two groups did not differ in locomotor activity, whereas at the third test occasion, bGH mice were significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain regions, decreased DA levels in the brain stem, and decreased levels of the DA metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon, compared with controls. In conclusion, bGH mice display more spontaneous locomotor activity than nontransgenic controls in a novel environment and possibly also a disturbed habituation process. The finding that bGH mice were also more sensitive to d-amphetamine-induced locomotor activity may suggest that the behavioral differences observed are related to differences in brain DA systems, indicating a hyperresponsiveness of these systems in bGH transgenic mice. These findings may constitute a neurochemical basis for the reported psychic effects of GH in humans.
Assuntos
Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Expressão Gênica , Hormônio do Crescimento/genética , Atividade Motora/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Bovinos , Dextroanfetamina/farmacologia , Dopamina/metabolismo , Etanol/farmacologia , Hormônio do Crescimento/fisiologia , Ácido Hidroxi-Indolacético/metabolismo , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Recompensa , Serotonina/metabolismoRESUMO
As a part of a prospective study (age, 0-2 years), the prognostic value of parent-reported symptoms relative to chronic otitis media with effusion (COME) was examined in a group of 122 infants. The occurrence of hearing loss, ear infection, mouth breathing, snoring and common cold was inventoried using a standardised questionnaire filled in by parents at 3-monthly intervals. Tympanometric and otoscopic records were combined for assessment of middle ear status. Subjects were categorized into three groups: none (n = 13), mild (n = 78) and severe (n = 31) COME. Analysis revealed that all symptoms in the first year of life were significantly associated with severe COME. In the second year, only hearing loss was associated with a higher risk for severe COME. The risk for severe COME increased when symptoms were combined. In conclusion, a questionnaire based on only symptoms during the first year of life may assist in screening and managing severe COME.
Assuntos
Otite Média com Derrame/diagnóstico , Pais , Distribuição por Idade , Área Programática de Saúde , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Otite Média com Derrame/epidemiologia , Prevalência , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To explore the incidence of treatment with ventilation tubes in the Netherlands in children from birth to 12 years of age in the period from 1990 to 1994. DESIGN: Secondary data analysis. METHODS: Data on bilateral treatment with ventilation tubes in 1990-1994 in the Netherlands were obtained from the National Medical Register of SIG Health Care Information. Incidence rates of the treatment in children aged 0-12 years were calculated using population estimates issued by the National Department of Statistics. RESULTS: Whereas from 1990 to 1992 the total number of bilateral inserted tubes increased from 39.923 to 51.615, a decrease to 48.635 was observed in 1994. The average incidence rate of treatment with ventilation tubes was 1.97% (range: 0.12%-5.08%) in children from birth to 12 years. Peak incidences were found around 2 years and 6 years of age. Prevalence rates of otitis media with effusion as found in the literature were higher, especially during infancy.