RESUMO
The role of neuropeptide S (NPS) in depression remains unclear. We examined the antidepressant-like effects of NPS infusions into the shell or core regions of the nucleus accumbens (NAc) and into the bed nucleus of the stria terminalis (BNST) of learned helplessness (LH) rats (an animal model of depression). Infusions of NPS (10 pmol/side) into the NAc shell, but not the NAc core and BNST, exerted antidepressant-like effects in the LH paradigm. Implying that behavioral deficits could be improved in the conditioned avoidance test. Coinfusion of SHA68 (an NPS receptor antagonist, 100 pmol/side) with NPS into the NAc shell blocked these effects. In contrast, NPS receptor antagonism by SHA68 in the BNST induced antidepressant-like effects. Infusions of NPS into the NAc shell or SHA68 into the BNST did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. These results suggest that excitatory and inhibitory actions by the NPS system are integral to the depression in LH animals.
Assuntos
Transtorno Depressivo/metabolismo , Desamparo Aprendido , Neuropeptídeos/metabolismo , Núcleo Accumbens/metabolismo , Núcleos Septais/metabolismo , Animais , Antidepressivos/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neuropeptídeos/administração & dosagem , Neuropeptídeos/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Oxazolidinonas/farmacologia , Pirazinas/farmacologia , Ratos Sprague-Dawley , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/metabolismo , Núcleos Septais/efeitos dos fármacosRESUMO
BACKGROUND: A relapse prevention program called the Information Technology Aided Relapse Prevention Programme in Schizophrenia (ITAREPS) has been developed and is reported to be highly effective. However the effectiveness was influenced by user adherence to the protocol of the program, the exact effectiveness and the role of the ITAREPS have been partially uncertain. OBJECTIVE: The purpose of this study is to evaluate the effectiveness of the ITAREPS excluding the effect of user adherence to the protocol of the program. METHOD: We attempted to perform a randomized controlled trial by the devised method with visiting nurse service. Outpatients with schizophrenia were randomized to the ITAREPS (n=22) or control group (n=23) and were observed for 12 months. RESULTS: The risk of rehospitalization was reduced in the ITAREPS group (2 [9.1%]) compared with the control group (8 [34.8%]) (hazard ratio=0.21, 95% CI 0.04-0.99, p=0.049; number needed to treat (NNT)=4, 95% CI 2.1-35.5). The mean number of inpatient days was significantly lower in the ITAREPS group (18.5 days) compared with the control group (88.8 days) (p=0.036). The ratio of the number of rehospitalizations to that of relapses was significantly lower (p=0.035) and the mean change in total BPRS scores at relapse from baseline was significantly less in the ITAREPS group (p=0.019). CONCLUSIONS: The relapse prevention effectiveness of the ITAREPS was high, and we confirmed that the ITAREPS, i.e., detecting signs of relapse and increasing medication during the warning state, is an effective intervention during the early stages of relapse.
Assuntos
Informática Médica/métodos , Readmissão do Paciente/estatística & dados numéricos , Esquizofrenia/terapia , Adulto , Antipsicóticos/uso terapêutico , Feminino , Hospitalização , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Prevenção Secundária , Estatísticas não ParamétricasRESUMO
BACKGROUND: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D(2) dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. METHODS: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D(2) receptor density (N = 4-10/condition/experiment). RESULTS: Chronic treatment with HAL led to significant increases in locomotor response and D(2) receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D(2) density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D(2) density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D(2) density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. CONCLUSIONS: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Haloperidol/farmacologia , Piperazinas/farmacologia , Psicoses Induzidas por Substâncias/fisiopatologia , Quinolonas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Animais , Aripiprazol , Corpo Estriado/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Inibidores da Captação de Dopamina , Assistência de Longa Duração , Masculino , Metanfetamina , Atividade Motora/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Sprague-DawleyRESUMO
AIM: In Japan, a new comprehensive forensic mental health service was established and enforced in 2005. However, the shortage of psychiatrists dedicated to this service is a problem. Therefore, we investigated the attitudes of general psychiatrists in Japan toward this field in order to develop measures for dealing with this issue. METHODS: Questionnaires were sent to 3205 psychiatric facilities in Japan in January 2007. The questions explored the experience of the respondents with forensic evaluations; the respondents' recognition of, experience with, and attitude toward the Medical Treatment and Supervision (MTS) Act; and attitudes toward forensic mental health in general. RESULTS: The data of 1770 respondents were analyzed in this study. Three main findings were obtained: psychiatrists generally had little experience with criminal responsibility evaluations, and a small percentage of psychiatrists tended to have conducted the majority of these evaluations; although psychiatrists widely recognized the enactment of the MTS Act, they were not sufficiently familiar with the details of the MTS Act; and in spite of a reluctance to address forensic mental health issues, the respondents harbored a general interest in these topics. CONCLUSIONS: Despite a general interest, general psychiatrists in Japan tend to possess insufficient knowledge of this subspecialty and lack experience in and opportunities to work in this subspecialty. The reluctance of psychiatrists to work in forensic mental health might be partly responsible for this situation. These results suggest that the enrichment of education systems for forensic psychiatry is necessary for the development of forensic psychiatry in Japan.
Assuntos
Atitude do Pessoal de Saúde , Psiquiatria Legal/estatística & dados numéricos , Pesquisas sobre Atenção à Saúde/estatística & dados numéricos , Feminino , Humanos , Japão , Masculino , Serviços de Saúde Mental/legislação & jurisprudência , Pessoa de Meia-IdadeRESUMO
Neuropeptide S (NPS) has been shown to promote arousal and anxiolytic-like effects, as well as facilitation of fear extinction. In rodents, NPS receptors (NPSR) are prominently expressed in brain structures involved in learning and memory. Here, we investigate whether exogenous or endogenous NPS signaling can modulate acquisition, consolidation, or recall of emotional, spatial, and contextual memory traces, using two common behavioral paradigms, inhibitory avoidance (IA) and novel object recognition. In the IA paradigm, immediate and delayed post-training central NPS administration dose dependently enhanced memory retention in mice, indicating that NPS may act during the consolidation phase to enhance long-term memory. In contrast, pre-training or pre-test NPS injections were ineffective, suggesting that NPS had no effect on IA memory acquisition or recall. Peripheral administration of a synthetic NPSR antagonist attenuated NPS-induced IA memory enhancement, showing pharmacological specificity. NPS also enhanced hippocampal-dependent non-aversive memory in the novel object recognition task. In contrast, NPSR knockout mice displayed deficits in IA memory, novel object recognition, and novel place or context recognition, suggesting that activity of the endogenous NPS system is required for memory formation. Blockade of adrenergic signaling by propranolol attenuated NPS-induced memory enhancement in the IA task, indicating involvement of central noradrenergic systems. These results provide evidence for a facilitatory role of NPS in long-term memory, independent of memory content, possibly by acting as a salience signal or as an arousal-promoting factor.
Assuntos
Encéfalo/metabolismo , Memória/fisiologia , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Norepinefrina/antagonistas & inibidores , Norepinefrina/deficiência , Animais , Aprendizagem da Esquiva/fisiologia , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Norepinefrina/metabolismo , Propranolol/farmacologiaRESUMO
Neuropeptide S (NPS) is known to produce anxiolytic-like effects and facilitate extinction of conditioned fear. Catecholaminergic neurotransmission in the medial prefrontal cortex (mPFC) has been suggested to be crucially involved in these brain functions. In the current study, we investigated the effect of NPS on the release of dopamine and serotonin in the mPFC by in vivo microdialysis in rats. Central administration of NPS dose-dependently enhanced extracellular levels of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid, with maximal effects lasting up to 120 min. In contrast, no effect on serotonergic neurotransmission was detected. Dopamine release in the mPFC has been previously linked to modulation of anxiety states and fear extinction. The present results may thus provide a physiological and anatomical basis for the reported effects of NPS on these behaviors.
Assuntos
Dopamina/metabolismo , Neuropeptídeos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Microdiálise/métodos , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismoRESUMO
Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose-dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.
Assuntos
Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Encéfalo , Neuropeptídeos/farmacologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/fisiopatologia , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Inibição Psicológica , Masculino , Camundongos , Camundongos Endogâmicos , Microdiálise/métodos , Neuropeptídeos/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Ratos , Ratos Sprague-DawleyRESUMO
Central administration of neuropeptide S (NPS) in rodents induces arousal and prolonged wakefulness as well as anxiolytic-like effects. NPS has also been implicated in modulation of cognitive functions and energy homeostasis. Here we present a comprehensive phenotypical analysis of mice carrying a targeted mutation in the NPS receptor (NPSR) gene. NPSR knockout mice were found to exhibit reduced exploratory activity when challenged with a novel environment, which might indicate attenuated arousal. We also observed attenuated late peak wheel running activity in NPSR knockout mice, representing reduced activity during the subjective evening. These mice also displayed increased anxiety-like behaviors when compared to their wildtype littermates, although analysis of anxiety behaviors was limited by genetic background influences. Unexpectedly, NPSR knockout mice showed enhanced motor performance skills. No phenotypical differences were detected in the forced-swim test, startle habituation and pre-pulse inhibition paradigms. Together, these data indicate that the endogenous NPS system might be involved in setting or maintaining behavioral arousal thresholds and that the NPS system might have other yet undiscovered physiological functions.
Assuntos
Comportamento Animal/fisiologia , Receptores de Neuropeptídeos/deficiência , Receptores de Neuropeptídeos/genética , Animais , Ansiedade/genética , Ansiedade/fisiopatologia , Percepção Auditiva/genética , Percepção Auditiva/fisiologia , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Depressão/genética , Depressão/fisiopatologia , Comportamento Exploratório/fisiologia , Habituação Psicofisiológica/genética , Habituação Psicofisiológica/fisiologia , Locomoção/genética , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/genética , Atividade Motora/fisiologia , Testes Neuropsicológicos , Fenótipo , Reflexo de Sobressalto/genética , Reflexo de Sobressalto/fisiologiaRESUMO
Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in various biological phenomena such as cell migration, neurogenesis, and tissue repair. We previously demonstrated that midkine-deficient (Mdk(-/-)) mice exhibited a delayed hippocampal development with impaired working memory and increased anxiety only at the age of 4 weeks. To assess whether midkine gene could play important roles in development and maintenance of central nervous system, we investigated biochemical and behavioral parameters in dopamine and glutamate neurotransmission of Mdk(-/-) mice. The Mdk(-/-) mice exhibited a hypodopaminergic state (i.e., decreased levels of dopamine and its receptors in the striatum) with no alterations of glutamatergic system (i.e., normal level of glutamate, glutamine, glycine, d-serine, l-serine, and NMDA receptors in the frontal cortex and hippocampus). We also found prepulse inhibition deficits reversed by clozapine and haloperidol in the Mdk(-/-) mice. Our results suggested that midkine deficiency may be related to neurochemical and behavioral dysfunctions in dopaminergic system.
Assuntos
Citocinas/deficiência , Dopamina/metabolismo , Inibição Neural/genética , Reflexo de Sobressalto/genética , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Comportamento Exploratório/fisiologia , Relações Interpessoais , Camundongos , Camundongos Endogâmicos C57BL/metabolismo , Camundongos Endogâmicos DBA/metabolismo , Camundongos Knockout , Midkina , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Inibição Neural/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Ensaio Radioligante/métodos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Trítio/metabolismoRESUMO
A deficient extinction of memory is particularly important in the regime of fear, where it limits the beneficial outcomes of treatments of anxiety disorders. Fear extinction is thought to involve inhibitory influences of the prefrontal cortex on the amygdala, although the detailed synaptic mechanisms remain unknown. Here, we report that neuropeptide S (NPS), a recently discovered transmitter of ascending brainstem neurons, evokes anxiolytic effects and facilitates extinction of conditioned fear responses when administered into the amygdala in mice. An NPS receptor antagonist exerts functionally opposing responses, indicating that endogenous NPS is involved in anxiety behavior and extinction. Cellularly, NPS increases glutamatergic transmission to intercalated GABAergic neurons in the amygdala via presynaptic NPS receptors on connected principal neurons. These results identify mechanisms of NPS in the brain, a key role of intercalated neurons in the amygdala for fear extinction, and a potential pharmacological avenue for treating anxiety disorders.
Assuntos
Tonsila do Cerebelo/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Interneurônios/fisiologia , Neuropeptídeos/farmacologia , Ácido gama-Aminobutírico/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Transmissão Sináptica/fisiologiaRESUMO
We used two-photon excitation with a near-infrared (NIR) laser microbeam to investigate activation of channelrhodopsin 2 (ChR2) in excitable cells for the first time to our knowledge. By measuring the fluorescence intensity of the calcium (Ca) indicator dye, Ca orange, at different wavelengths as a function of power of the two-photon excitation microbeam, we determined the activation potential of the NIR microbeam as a function of wavelength. The two-photon activation spectrum is found to match measurements carried out with single-photon activation. However, two-photon activation is found to increase in a nonlinear manner with the power density of the two-photon laser microbeam. This approach allowed us to activate different regions of ChR2-sensitized excitable cells with high spatial resolution. Further, in-depth activation of ChR2 in a spheroid cellular model as well as in mouse brain slices was demonstrated by the use of the two-photon NIR microbeam, which was not possible using single-photon activation. This all-optical method of identification, activation, and detection of ChR2-induced cellular activation in genetically targeted cells with high spatial and temporal resolution will provide a new method of performing minimally invasive in-depth activation of specific target areas of tissues or organisms that have been rendered photosensitive by genetic targeting of ChR2 or similar photo-excitable molecules.
Assuntos
Raios Infravermelhos , Ativação do Canal Iônico/efeitos da radiação , Lasers , Neurônios/citologia , Neurônios/metabolismo , Fótons , Animais , Linhagem Celular , Channelrhodopsins , Fluorescência , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Compostos Orgânicos/metabolismoRESUMO
Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca2+ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPS-induced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.
Assuntos
Oxazolidinonas/farmacologia , Pirazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/metabolismo , Oxazolidinonas/síntese química , Oxazolidinonas/farmacocinética , Pirazinas/síntese química , Pirazinas/farmacocinéticaRESUMO
Panic disorder is a common anxiety disorder characterized by sudden and recurrent panic attacks. Previous studies have indicated significant genetic contributions and a susceptibility locus for panic disorder has been mapped to human chromosome 7p 15. The receptor for Neuropeptide S (NPS) is located in the same genomic region while NPS is known to produce arousal and anxiolytic-like effects in rodents. Here we report that a coding polymorphism in the Neuropeptide S receptor (NPSR) is associated with panic disorder in male patients of Japanese ancestry. The polymorphism (Asn(107)Ile) results in a gain-of-function of the receptor protein by increasing the agonist sensitivity about tenfold. The allele representing the less active isoform (NPSR Asn(107)) was found under-represented in male panic disorder patients, indicating a potential protective function of the protein. Two unrelated groups of patients diagnosed with schizophrenia or attention-deficit/hyperactivity disorder (ADHD) showed no association of particular NPSR alleles with the disorders. These results provide evidence for a gender-specific effect of NPSR in the pathogenesis of panic disorder.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno de Pânico/genética , Polimorfismo Genético/genética , Receptores Acoplados a Proteínas G/genética , Esquizofrenia/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Família , Feminino , Frequência do Gene , Genótipo , Alemanha/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/psicologia , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Psicologia do Esquizofrênico , Caracteres SexuaisRESUMO
Neuropeptide S (NPS) is a recently identified bioactive peptide that modulates stress and arousal. NPS is expressed in a few discrete nuclei in the brainstem, such as the pericoerulear (locus coeruleus (LC)) area and the parabrachial nucleus. NPS activates its cognate G protein-coupled receptor at low nanomolar agonist concentrations and induces elevation of intracellular Ca2+ and cAMP, therefore acting as an excitatory transmitter. The NPS receptor is widely expressed in the brain, including regions known to regulate stress responses such as hypothalamus, thalamus, amygdala and limbic cortex. We have recently reported that the NPS system can modulate stress responses and induce wakefulness based on a battery of behavioral tests. Activation of NPS receptors induces arousal and reduces all sleep stages. At the same time, NPS produces anxiolytic-like effects in rodents. These studies indicate that the NPS system has a unique pharmacological profile to promote both anxiolytic and arousal effects. NPS might interact with other hypothalamic neuropeptide systems that are known to be involved in stress and appetite control and thus might be a valuable target for development of a new class of drugs to treat anxiety disorders.
Assuntos
Ansiedade/metabolismo , Nível de Alerta , Tronco Encefálico/metabolismo , Neuropeptídeos/metabolismo , Estresse Psicológico/metabolismo , Sequência de Aminoácidos , Animais , Ansiedade/fisiopatologia , Humanos , Dados de Sequência Molecular , Neuropeptídeos/biossíntese , Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo , Transdução de Sinais , Sono , VigíliaRESUMO
N-Methyl-d-aspartate (NMDA) receptor antagonists are known to induce schizophrenia-like psychotic symptoms and cognitive deficits in humans, and have been shown to cause neuronal damage in the posterior cingulate gyrus (PCG) of rodents. Patients with chronic schizophrenia exhibit generalized cognitive deficits, but it remains unclear whether or not the PCG is related to their cognitive dysfunction. To determine what biochemical changes may occur in the PCG of patients with chronic schizophrenia, and to ascertain whether or not such abnormalities may be related to the incidence of cognitive deficits, we obtained cognitive scores and proton magnetic resonance spectra (MRS) from the PCG and the left and right medial temporal lobes (MTL) of 19 patients with schizophrenia and 18 age- and sex-matched normal healthy controls. Compared to the normal controls, the patients with chronic schizophrenia showed significantly worse cognitive performance on verbal and visual memory tests, verbal fluency tests, and the Trail Making Test. The ratio of N-acetylaspartate to creatine and phosphocreatine (NAA/Cr) in the PCG of the patients was significantly lower than that of the controls. Moreover, the NAA/Cr in the PCG of the healthy controls exhibited age-related decline, whereas in the patients with schizophrenia, the corresponding values were consistently low, regardless of age. These findings are thus in accord with current speculation about neuronal dysfunction in the PCG based on the NMDA hypofunction hypothesis regarding the pathophysiology of chronic schizophrenia.
Assuntos
Transtornos Cognitivos/epidemiologia , Giro do Cíngulo/metabolismo , Esquizofrenia/epidemiologia , Esquizofrenia/metabolismo , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Escalas de Graduação Psiquiátrica Breve , Doença Crônica , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Fosfocreatina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/fisiopatologia , Índice de Gravidade de Doença , Lobo Temporal/metabolismo , Lobo Temporal/fisiopatologia , Escalas de WechslerRESUMO
A certain type of personality is at risk for developing psychiatric diseases. Several lines of evidence support the interaction between brain angiotensins and central catecholamine systems, and suggest that angiotensin I-converting enzyme (ACE) may be a reasonable candidate gene for psychiatric disorders. The present study examined the possibility that ACE insertion (I)/deletion (D) functional polymorphism might be associated with particular personality traits. Healthy Japanese subjects (N=184) were administered the Temperament and Character Inventory (TCI) and the NEO Personality Inventory Revised version (NEO-PI-R), and their ACE I/D polymorphisms were determined. There was an ethnic difference in the genetic distribution of ACE I/D between Japanese (D=34.5%) and Caucasians (D=55.2%). We found that the scores of novelty seeking (NS) in the Low-ACE group (II genotype) of healthy female subjects were significantly lower than those in the High-ACE group (ID or DD genotype) (p=0.018). Our findings suggested that the ACE I/D polymorphism might be associated with the NS personality trait in females, but not males. Taking into account the effects of multiple comparisons, this result should be interpreted with caution, and needs confirmation in a larger sample.
Assuntos
Comportamento Exploratório , Peptidil Dipeptidase A/genética , Personalidade/genética , Polimorfismo Genético , Caracteres Sexuais , Adulto , Alelos , Análise de Variância , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Inventário de Personalidade/estatística & dados numéricosRESUMO
Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant (p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.
Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Polimorfismo Genético/genética , Psicoses Induzidas por Substâncias/etiologia , Psicoses Induzidas por Substâncias/genética , Quinona Redutases/genética , Adulto , Primers do DNA , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Mutação Puntual/genética , Regiões Promotoras Genéticas/genética , Mapeamento por RestriçãoRESUMO
We have recently shown that Neuropeptide S (NPS) can promote arousal and induce anxiolytic-like effects after central administration in rodents. Another study reported a number of natural polymorphisms in the human NPS receptor gene. Some of these polymorphisms were associated with increased risk of asthma and possibly other forms of atopic diseases, but the physiological consequences of the mutations remain unclear. One of the polymorphisms produces an Asn-Ile exchange in the first extracellular loop of the receptor protein, and a C-terminal splice variant of the NPS receptor was found overexpressed in human asthmatic airway tissue. We sought to study the pharmacology of the human receptor variants in comparison with the murine receptor protein. Here, we report that the N107I polymorphism in the human NPS receptor results in a gain-of-function characterized by an increase in agonist potency without changing binding affinity in NPSR Ile107. In contrast, the C-terminal splice variant of the human NPS receptor shows a pharmacological profile similar to NPSR Asn107. The mouse NPS receptor, which also carries an Ile residue at position 107, displays an intermediate pharmacological profile. Structure-activity relationship studies show that the amino terminus of NPS is critical for receptor activation. The altered pharmacology of the Ile107 isoform of the human NPS receptor implies a mechanism of enhanced NPS signaling that might have physiological significance for brain function as well as peripheral tissues that express NPS receptors.
Assuntos
Variação Genética , Neuropeptídeos/farmacologia , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/metabolismo , Sequência de Aminoácidos , Animais , Asparagina/química , Células CACO-2 , Cálcio/metabolismo , Divisão Celular/efeitos dos fármacos , Linhagem Celular , AMP Cíclico/análise , AMP Cíclico/biossíntese , Relação Dose-Resposta a Droga , Éxons , Genes Reporter , Células HT29 , Humanos , Isoleucina/química , Luciferases/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Polimorfismo Genético , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ensaio Radioligante , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/genética , Relação Estrutura-AtividadeRESUMO
Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.