RESUMO
We investigated the role of serotonin(2C) receptor-mediated feedback mechanisms in the response to citalopram in C57BL/6 and DBA/2 mice, which are respectively responders and non-responders to selective serotonin reuptake inhibitors in the forced swimming test. The microdialysis technique was used to assess changes in extracellular serotonin and GABA in the mouse dorsal raphé (DR). Citalopram (1.25-20 mg/kg) raised extracellular serotonin and GABA in the DR of both mouse strains. These effects were abolished by depleting brain serotonin with p-chlorophenylalanine (300 mg/kg × 3). Systemic and/or intra-DR infusion of the serotonin(2C) receptor antagonist 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (1 mg/kg and 0.1 µM, respectively) enhanced citalopram's effect on extracellular serotonin in the DR and medial prefrontal cortex and abolished the rise of GABA in the DR of DBA/2 mice but had no effect in C57BL/6 mice. The serotonin(2C) receptor agonist Ro60-0175 (0.03-3.0 mg/kg) reduced extracellular serotonin and raised GABA in the DR of DBA/2 mice but had much less effect in C57BL/6 mice. These findings show that the sensitivity of serotonin(2C) receptors determines the efficacy of augmentation strategies aimed at enhancing the effect of serotonin reuptake inhibitors on extracellular serotonin through the suppression of serotonin(2C) receptor-mediated feedback control of serotonin neurons.
Assuntos
Neurônios/metabolismo , Receptor 5-HT2C de Serotonina/fisiologia , Serotonina/metabolismo , Aminopiridinas/farmacologia , Animais , Citalopram/farmacologia , Etilaminas/farmacologia , Espaço Extracelular/metabolismo , Retroalimentação Fisiológica , Fenclonina/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Microdiálise , Neurônios/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Especificidade da Espécie , Ácido gama-Aminobutírico/metabolismoRESUMO
Motor skill is a specific area of disability of Rett syndrome (RTT), a rare disorder occurring almost exclusively in girls, caused by loss-of-function mutations of the X-linked methyl-CpG-binding protein2 (MECP2) gene, encoding the MECP2 protein, a member of the methyl-CpG-binding domain nuclear proteins family. Brain 5-HT, which is defective in RTT patients and Mecp2 mutant mice, regulates motor circuits and SSRIs enhance motor skill learning and plasticity. In the present study, we used heterozygous (Het) Mecp2 female and Mecp2-null male mice to investigate whether fluoxetine, a SSRI with pleiotropic effects on neuronal circuits, rescues motor coordination deficits. Repeated administration of 10 mg/kg fluoxetine fully rescued rotarod deficit in Mecp2 Het mice regardless of age, route of administration or pre-training to rotarod. The motor improvement was confirmed in the beam walking test while no effect was observed in the hanging-wire test, suggesting a preferential action of fluoxetine on motor coordination. Citalopram mimicked the effects of fluoxetine, while the inhibition of 5-HT synthesis abolished the fluoxetine-induced improvement of motor coordination. Mecp2 null mice, which responded poorly to fluoxetine in the rotarod, showed reduced 5-HT synthesis in the prefrontal cortex, hippocampus and striatum, and reduced efficacy of fluoxetine in raising extracellular 5-HT as compared to female mutants. No sex differences were observed in the ability of fluoxetine to desensitize 5-HT1A autoreceptors upon repeated administration. These findings indicate that fluoxetine rescues motor coordination in Mecp2 Het mice through its ability to enhance brain 5-HT and suggest that drugs enhancing 5-HT neurotransmission may have beneficial effects on motor symptoms of RTT.
Assuntos
Encéfalo/metabolismo , Fluoxetina/uso terapêutico , Proteína 2 de Ligação a Metil-CpG/deficiência , Desempenho Psicomotor/efeitos dos fármacos , Síndrome de Rett/metabolismo , Serotonina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Feminino , Fluoxetina/farmacologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desempenho Psicomotor/fisiologia , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/genética , Teste de Desempenho do Rota-Rod/métodos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Blockade of NMDA receptors by intracortical infusion of 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) increases glutamate (GLU) and serotonin (5-HT) release in the medial prefrontal cortex and impairs attentional performance in the 5-choice serial reaction time task. These effects are prevented by the 5-HT(2A) receptor antagonist, (R)-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol (M100907). We explored the roles of endogenous 5-HT and 5-HT(1A) and 5-HT(2C) receptors in the mechanisms by which M100907 suppresses CPP-induced release of cortical GLU and 5-HT using in vivo microdialysis. CPP raised extracellular GLU and 5-HT by about 250% and 170% respectively. The 5-HT synthesis inhibitor, p-chlorophenylalanine (300 mg/kg), prevented M100907 suppressing CPP-induced GLU release. The effect of M100907 on these rises of GLU and 5-HT and attentional performance deficit was mimicked by the 5-HT(2C) receptor agonist, (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine fumarate, (Ro60-0175, 30 microg/kg) while intra-mPFC (SB242084, 6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline, 0.1 microM), a 5-HT(2C) receptor antagonist, prevented the effect of M100907 on extracellular GLU. The 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxenide trihydrochloride (100 microM) abolished the effect of M100907 on the CPP-induced 5-HT release. The data show that blockade of 5-HT(2A) receptors is not sufficient to suppress the CPP-induced rise of extracellular GLU and 5-HT and suggest that M100907 suppresses GLU release induced by CPP by enhancing the action of endogenous 5-HT on 5-HT(2C) receptors.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Fluorbenzenos/farmacologia , Ácido Glutâmico/metabolismo , Piperidinas/farmacologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Animais , Comportamento Animal , Cromatografia Líquida de Alta Pressão/métodos , Etilaminas/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Indóis/farmacologia , Masculino , Microdiálise/métodos , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina , Fatores de TempoRESUMO
We recently found that the response of DBA/2 mice to SSRIs in the forced swim test (FST) was impaired and they also had a smaller basal and citalopram-stimulated increase in brain extracellular serotonin (5-HT) than 'responder' strains. We employed intracerebral microdialysis, FST and selective antagonists of 5-HT1A and 5-HT2C receptors to investigate whether enhancing the increase in extracellular 5-HT reinstated the anti-immobility effect of citalopram in the FST. WAY 100635 (0.3 mg/kg s.c.) or SB 242084 (1 mg/kg s.c.), respectively a selective 5-HT1A and 5-HT2C receptor antagonist, raised the effect of citalopram (5 mg/kg) on extracellular 5-HT in the medial prefrontal cortex of DBA/2N mice (citalopram alone 5.2+/-0.3 fmol/20 microl, WAY 100635+citalopram 9.9+/-2.1 fmol/20 microl, SB 242084+ citalopram 7.6+/-1.0 fmol/20 microl) to the level reached in 'responder' mice given citalopram alone. The 5-HT receptor antagonists had no effect on the citalopram-induced increase in extracellular 5-HT in the dorsal hippocampus. The combination of citalopram with WAY 100635 or SB 242084 significantly reduced immobility time in DBA/2N mice that otherwise did not respond to either drug singly. Brain levels of citalopram in mice given citalopram alone or with 5-HT antagonists did not significantly differ. The results confirm that impaired 5-HT transmission accounts for the lack of effect of citalopram in the FST and suggest that enhancing the effect of SSRIs on extracellular 5-HT, through selective blockade of 5-HT1A and 5-HT2C receptors, could be a useful strategy to restore the response in treatment-resistant depression.
Assuntos
Córtex Cerebral/citologia , Líquido Extracelular/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Serotonina/metabolismo , Aminopiridinas/farmacologia , Análise de Variância , Animais , Antidepressivos/farmacocinética , Córtex Cerebral/efeitos dos fármacos , Citalopram/farmacocinética , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Líquido Extracelular/efeitos dos fármacos , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Microdiálise/métodos , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologiaRESUMO
RATIONALE: Cognitive impairment in schizophrenia is particularly evident in the domains of attention and executive functions. Atypical antipsychotics are somewhat more effective than conventional antipsychotics in improving cognitive functioning in these patients. OBJECTIVE: The aim of this study was to compare the effects of conventional and atypical antipsychotics in a model of attentional performance deficit of schizophrenia induced by blockade of N-methyl-D: -aspartate (NMDA) receptors in the medial prefrontal cortex. MATERIALS AND METHODS: Attentional performance was assessed using the five-choice serial reaction time task. The task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responding), decision time (measured by correct response latency), and omissions. Haloperidol and clozapine were given intraperitoneally (IP) to animals that had received vehicle or a competitive NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP), directly into the medial prefrontal cortex. RESULTS: Fifty nanograms/side of CPP reduced accuracy (% correct responses) and increased anticipatory and perseverative responding. Haloperidol (0.03 mg/kg IP) reduced the CPP-induced anticipatory and perseverative overresponding but not the impairment in accuracy. In contrast, clozapine (2.5 mg/kg IP) reversed the decrease in accuracy and impulsivity (anticipatory responding) but not perseverative overresponding. CPP increased decision time and omissions, but these effects were not affected by either haloperidol or clozapine. CONCLUSIONS: The effects on "impulsivity" and "compulsive perseveration" in a rat model of attentional and executive deficit of schizophrenia might differentiate conventional and atypical antipsychotics. Antagonistic activity at 5-HT(2A) receptors may best explain the facilitatory effects of clozapine on cognition.
Assuntos
Atenção/efeitos dos fármacos , Clozapina/farmacologia , Haloperidol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Análise de Variância , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Clozapina/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Haloperidol/administração & dosagem , Injeções Intraperitoneais , Masculino , Microinjeções , Piperazinas/administração & dosagem , Piperazinas/toxicidade , Córtex Pré-Frontal/metabolismo , Ratos , Tempo de Reação/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Aprendizagem Seriada/efeitos dos fármacos , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacologiaRESUMO
We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Depressão/psicologia , Atividade Motora/efeitos dos fármacos , Paroxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/fisiologia , Natação/psicologia , Animais , Química Encefálica/efeitos dos fármacos , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Paroxetina/metabolismo , Serotonina/biossíntese , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Especificidade da Espécie , Triptofano/farmacologiaRESUMO
Polymorphism of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of brain serotonin (5-HT), is associated with less synthesis of brain 5-HT in DBA/2J and BALB/c than in C57BL/6J and 129/Sv mice. We selected the forced swimming test, a mouse model used to assess the antidepressant potential of drugs, and neurochemical techniques to study strain differences in the response to citalopram, a selective 5-HT reuptake inhibitor. Citalopram reduced immobility time in C57BL/6J and 129/Sv mice but had no such effect in DBA/2J and BALB/c mice. The drug reduced accumulation of 5-hydroxytryptophan (5-HTP), an indicator of 5-HT synthesis, in C57BL/6J and 129/Sv mice but much less in DBA/2J and BALB/c mice. Pretreatment with tryptophan raised 5-HTP accumulation and reinstated the antidepressant-like effect of citalopram in DBA/2J and BALB/c mice, whereas pharmacological inhibition of 5-HT synthesis prevented the effect of citalopram in C57BL/6J and 129/Sv mice. Because there were no strain differences in catecholamine synthesis, locomotor activity, and brain levels of citalopram at the end of the behavioral test, the results suggest that the failure of citalopram to reduce immobility time in DBA/2J and BALB/c mice is attributable to genotype-dependent impairment of 5-HT synthesis. Interstrain comparisons could probably be a useful strategy for understanding the mechanisms underlying the response to selective serotonin reuptake inhibitors.
Assuntos
Citalopram/farmacologia , Depressão/enzimologia , Depressão/genética , Atividade Motora/fisiologia , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Animais , Antidepressivos de Segunda Geração/farmacologia , Primers do DNA , Modelos Animais de Doenças , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Atividade Motora/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético , Serotonina/metabolismo , Especificidade da Espécie , NataçãoRESUMO
Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia. Several lines of evidence suggest a pathophysiological role for glutamate NMDA receptors in the prefrontal cortex in schizophrenia and associated disorders in attention and executive functioning. We investigated how the interactions between 5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC) contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT(1A) receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats. The data show that 5-HT1A and 5-HT2A receptors in the mPFC exert opposing actions on attentional functioning and demonstrate a dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration.
Assuntos
Atenção/fisiologia , Comportamento Compulsivo/fisiopatologia , Comportamento Impulsivo/fisiopatologia , Córtex Pré-Frontal/fisiologia , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Análise de Variância , Animais , Atenção/efeitos dos fármacos , Comportamento Animal , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluorbenzenos/farmacologia , Masculino , Piperazinas/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Tempo de Reação/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
The slow onset of antidepressant drugs' effects is thought to reflect the time required for the development of adaptive changes such as desensitization of presynaptic autoreceptors controlling the release of neurotransmitters. Using in vivo microdialysis in conscious rats, we studied the effect of a continuous infusion of the selective noradrenaline (NA) reuptake inhibitor reboxetine on extracellular concentrations of NA. Doses of 10 mg/kg/day reboxetine through subcutaneous osmotic pumps for 2 days increased extracellular NA by 272% in the dorsal hippocampus (DH) of rats. NA rose significantly more in rats given reboxetine for 7 (469%) and 14 (437%) days. Intraperitoneal injection of 30 microg/kg clonidine, an alpha2-adrenoceptor agonist, reduced the release of NA to 49% of basal levels in rats given vehicle or reboxetine for 2 days, but this effect was markedly less in rats given reboxetine for 7 and 14 days. Likewise, the effect of intrahippocampal infusion of clonidine (0.05 and 0.2 microM) on extracellular NA was significantly attenuated in rats given reboxetine for 7 and 14 days, whereas the injection of 0.6 nmol clonidine into the locus coeruleus caused similar reductions of extracellular NA in the DH and prefrontal cortex (PFC) of rats infused with vehicle (DH -64%; PFC -42%) and reboxetine (DH -45%; PFC -28%) for 14 days. The results indicate that chronic treatment markedly enhances the effect of reboxetine on extracellular NA in the DH and suggest that this effect may be due to the desensitization of hippocampal alpha2-adrenoceptors.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Dendritos/metabolismo , Hipocampo/metabolismo , Morfolinas/farmacologia , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Inibidores da Captação Adrenérgica/administração & dosagem , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Clonidina/administração & dosagem , Clonidina/farmacologia , Dendritos/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Bombas de Infusão Implantáveis , Injeções Intraperitoneais , Locus Cerúleo/fisiologia , Masculino , Microinjeções , Morfolinas/administração & dosagem , Ratos , ReboxetinaRESUMO
RATIONALE: Converging evidence implicates glutamate neurotransmission in attention and inhibitory response control. OBJECTIVE: To investigate how the background genotype contributes to glutamate's effects on attention and response control, we examined how phencyclidine (PCP) affected the performance of a five-choice serial reaction time (5-CSRT) task in two inbred mouse strains, C57BL/6N and DBA/2N. We also tested a potent mGlu(2/3) receptor agonist, LY379268, against PCP's effects. METHODS: Mice were trained on a 5-CSRT task, which measures visual attention and response control until they reached asymptotic performance. Both strains of mice were then injected intraperitoneally with 0.5, 1.5 or 3.0 mg/kg PCP. Doses of 1.0 and 3.0 mg/kg of LY379268 were injected subcutaneously to vehicle or PCP-treated mice. RESULTS: At asymptotic performance DBA/2N mice were less accurate and made more anticipatory responses than C57BL/6N. PCP impaired accuracy (% correct) and increased perseverative responses of DBA/2N mice at 1.5 mg/kg. However, at doses up to 3.0 mg/kg it had no effect on these measures in C57BL/6N. In DBA/2N mice 1.5 mg/kg PCP increased anticipatory responses far more than 3.0 mg/kg in C57BL/6N mice. No dose of LY379268 prevented the PCP-induced accuracy deficit of DBA/2N mice. The PCP-induced anticipatory and perseverative responding of DBA/2N mice was reduced by 3.0 mg/kg LY379268, while 1.0 and 3.0 mg/kg reduced anticipatory responding in C57BL/6N. CONCLUSIONS: The background genotype may determine the effects of PCP on attentional performance and the results confirm the importance of glutamate transmission in some aspects of this performance.
Assuntos
Aminoácidos/farmacologia , Atenção/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Animais , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Especificidade da EspécieRESUMO
The alpha(2)-adrenoceptor antagonist idazoxan may improve motor symptoms in Parkinson's disease and experimental Parkinsonism. We studied the effect of idazoxan on haloperidol-induced catalepsy in rats, an animal model of the drug-induced extrapyramidal side effects in man. Catalepsy was induced by a subcutaneous (s.c.) injection of haloperidol (1 mg/kg) and measured by the bar test for a maximum of 5 min. At 3 h after haloperidol, rats were given 0.16-5.0 mg/kg s.c. idazoxan, and descent latency was measured 1 h later. Idazoxan potently reversed haloperidol-induced catalepsy with an ED(50) of 0.25 mg/kg. This effect was mimicked by the selective alpha(2)-adrenoceptor antagonist RS-15385-197 (0.3 and 1 mg/kg orally). We assessed how dopaminergic mechanisms were involved in the anticataleptic effect of idazoxan by studying its effect on dopamine (DA) release in the striatum, with the microdialysis technique in conscious rats. Idazoxan (0.3 and 2.5 mg/kg) had no effect on extracellular DA and did not modify the rise of extracellular DA induced by haloperidol, indicating that changes of striatal DA release were not involved in the reversal of catalepsy. The anticataleptic effect of 2.5 mg/kg idazoxan (haloperidol+vehicle 288+/-8 s, haloperidol+idazoxan 47+/-22 s) was attenuated in rats given an intraventricular injection of 150 microg of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (haloperidol+vehicle 275+/-25 s, haloperidol+idazoxan 137+/-28 s). The 5-HT(1A) receptor antagonist WAY100 635 (0.1 mg/kg s.c.) did not affect the anticataleptic effect of idazoxan. The results suggest that idazoxan reversed haloperidol-induced catalepsy by a mechanism involving blockade of alpha(2)-adrenoceptors and, at least in part, 5-HT neurons.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Catalepsia/tratamento farmacológico , Dopamina/metabolismo , Idazoxano/uso terapêutico , Serotonina/metabolismo , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Haloperidol/toxicidade , Idazoxano/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de SerotoninaRESUMO
We investigated whether 5-HT2A receptors contribute to the control of attentional performance by glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC). We examined the effects of NMDA receptor blockade in the mPFC on attentional performance by infusing a competitive glutamate NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) into the mPFC of rats performing a task of divided and sustained visual attention. The five-choice serial reaction time task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responses) and speed. A dose of 10 ng CPP injected bilaterally into the mPFC increased anticipatory and perseverative responding; 50 ng reduced accuracy. Increasing the stimulus duration alleviated the CPP-induced accuracy deficit but did not reduce its effects on anticipatory and perseverative responses. CPP at 50 ng caused motor hyperactivity whereas lower doses had no effect. [R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol] (M100907) (M100907), a 5-HT2A receptor antagonist, injected subcutaneously at 10 and 40 microg/kg, had no effect on accuracy but dose dependently reversed the impairment induced by 50 ng CPP. Both doses of M100907 completely abolished CPP-induced anticipatory but not perseverative over-responding. At the dose of 40 microg/kg M100907 reversed CPP-induced motor hyperactivity. This study provides evidence that the prefronto-cortical glutamate NMDA system may make an important contribution to the control of attention and executive functions. It also indicates that 5-HT2A receptors may serve to optimize attentional selectivity and improve some aspects of executive control.
Assuntos
Atenção/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluorbenzenos/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Injeções Subcutâneas , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Ratos , Tempo de Reação/efeitos dos fármacos , Aprendizagem Seriada/efeitos dos fármacosRESUMO
The therapeutic effect of an antidepressant drug takes at least 2 to 3 weeks to develop and a significant proportion of patients have no or only partial benefit regardless of the class of antidepressant used. Research into the neurobiological basis of antidepressant action has suggested new strategies to improve the antidepressant effect. Recent microdialysis studies show that hypofunction of the presynaptic autoreceptors enhances the increase of extracellular serotonin (5-HT) induced by selective serotonin reuptake inhibitors (SSRIs) so it has been suggested that the antidepressant effect may be speeded up by blockade of the autoreceptors. The similarity between the synaptic mechanisms controlling serotonergic and noradrenergic transmission has stimulated preclinical research into the role of presynaptic alpha(2)-adrenoceptors in the effect of noradrenaline (NA) reuptake inhibitors (NRIs) on NA availability at central synapses. The microdialysis studies reviewed here indicate that NRIs including desipramine, reboxetine and atomoxetine, the mixed 5-HT/NA reuptake inhibitors sibutramine, duloxetine, venlafaxine or the NA/DA reuptake inhibitor amineptine, increased extracellular NA in various regions of the rat brain. The effect was enhanced by chronic treatment and even more by the co-administration of alpha(2)-adrenoceptor antagonists. The results support the theory that desensitization of the alpha(2)-adrenoceptor contributes to enhancing the effect of NRIs seen after chronic administration and may account for the slow onset of the antidepressant effect. Finally, they suggest that co-administration of an alpha(2)-adrenoceptor antagonist may improve the therapeutic effect of NRI.
Assuntos
Antidepressivos/farmacologia , Microdiálise/métodos , Terminações Pré-Sinápticas/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Animais , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Espaço Extracelular/efeitos dos fármacos , Humanos , Modelos Neurológicos , Norepinefrina/metabolismo , Terminações Pré-Sinápticas/fisiologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacosRESUMO
Executive functions are an emerging propriety of neuronal processing in circuits encompassing frontal cortex and other cortical and subcortical brain regions such as basal ganglia and thalamus. Glutamate serves as the major neurotrasmitter in these circuits where glutamate receptors of NMDA type play key role. Serotonin and dopamine afferents are in position to modulate intrinsic glutamate neurotransmission along these circuits and in turn to optimize circuit performance for specific aspects of executive control over behavior. In this review, we focus on the 5-choice serial reaction time task which is able to provide various measures of attention and executive control over performance in rodents and the ability of prefrontocortical and striatal serotonin 5-HT1A, 5-HT2A, and 5-HT2C as well as dopamine D1- and D2-like receptors to modulate different aspects of executive and attention disturbances induced by NMDA receptor hypofunction in the prefrontal cortex. These behavioral studies are integrated with findings from microdialysis studies. These studies illustrate the control of attention selectivity by serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D1- but not D2-like receptors and a distinct contribution of these cortical and striatal serotonin and dopamine receptors to the control of different aspects of executive control over performance such as impulsivity and compulsivity. An association between NMDA antagonist-induced increase in glutamate release in the prefrontal cortex and attention is suggested. Collectively, this review highlights the functional interaction of serotonin and dopamine with NMDA dependent glutamate neurotransmission in the cortico-striatal circuitry for specific cognitive demands and may shed some light on how dysregulation of neuronal processing in these circuits may be implicated in specific neuropsychiatric disorders.
Assuntos
Atenção/fisiologia , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/fisiologia , Função Executiva/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Neurônios Serotoninérgicos/fisiologia , Animais , Comportamento de Escolha/fisiologia , Vias Neurais/metabolismo , Tempo de Reação/fisiologia , RoedoresRESUMO
We investigated the interaction between the corticostriatal glutamatergic afferents and dopamine D1-like and D2-like receptors in the dorsomedial striatum (dm-STR) in attention and executive response control in the five-choice serial reaction time (5-CSRT) task. The competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) injected in the mPFC impaired accuracy and increased premature and perseverative responding, raising GLU, DA, and GABA release in the dm-STR. The D1-like antagonist SCH23390 injected in the dm-STR reversed the CPP-induced accuracy deficit but did not affect the increase in perseverative responding. In contrast, the D2-like antagonist haloperidol injected in the dm-STR reduced the CPP-induced increase in perseverative responding but not the accuracy deficit. The different roles of dorsal striatal D1-like and D2-like receptor were further supported by the finding that activation of D1-like receptor in the dm-STR by SKF38393 impaired accuracy but not perseverative responding while the D2-like agonist quinpirole injected in the dm-STR increased perseverative responding but did not affect accuracy. These findings suggest that integration of cortical information by D1-like receptors in the dm-STR is a key mechanism of the input selection process of attention while the integration of corticostriatal signals by D2-like receptors preserves the ability to switch from one act/response to the next in a complex motor sequence, thus providing for behavioral flexibility.
Assuntos
Atenção/fisiologia , Comportamento de Escolha/fisiologia , Corpo Estriado/metabolismo , Tempo de Reação/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Aminoácidos/metabolismo , Análise de Variância , Animais , Atenção/efeitos dos fármacos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comportamento de Escolha/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Masculino , Microdiálise , Piperazinas/efeitos adversos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos , Tempo de Reação/efeitos dos fármacosRESUMO
Trace amines (TAs) such as ß-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).
Assuntos
Anfetamina/farmacologia , Monoaminas Biogênicas/fisiologia , Química Encefálica/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/fisiologia , Transmissão Sináptica/fisiologia , Compostos de Anilina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos , Imidazóis/farmacologia , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Técnicas de Patch-Clamp , Fenótipo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
RATIONALE: Blockade of N-methyl-d-aspartic acid (NMDA) receptors in the rat medial prefrontal cortex (mPFC) impairs performance in the five-choice serial reaction time task (5-CSRTT) and increases glutamate (GLU) release. Recent research suggests that excessive GLU release may be critical for attention deficits. OBJECTIVES: We tested this hypothesis by investigating the effects of the atypical antipsychotics sertindole and clozapine on 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP)-induced performance deficits in the 5-CSRTT and on the CPP-induced GLU release in the mPFC. METHODS: The 5-CSRTT, a test of divided and sustained visual attention providing indices of attentional functioning (accuracy of visual discrimination), response control (anticipatory and perseverative responses) and intracortical microdialysis in conscious rats were used to investigate the effects of sertindole and clozapine. RESULTS: Low doses of sertindole (0.02-0.32 mg/kg) prevented CPP-induced accuracy deficits, anticipatory over-responding and the rise in GLU release. In contrast, doses ranging from 0.6 to 2.5 mg/kg had no effect or even enhanced the effect of CPP on anticipatory responding. Similarly, 2.5 mg/kg sertindole was unable to reverse CPP-induced rise in GLU release. Clozapine (2.5 mg/kg) prevented accuracy deficits and the increase in anticipatory responding and abolished the rise in GLU release induced by CPP. CONCLUSIONS: These findings show that the ameliorating effects of sertindole and clozapine on NMDA receptor dependent attention deficit is associated with suppression in GLU release in the mPFC. This supports the proposal that suppression in GLU release might be a target for the development of novel drugs aimed at counteracting some aspects of cognitive deficits of schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Atenção/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Imidazóis/farmacologia , Indóis/farmacologia , Piperazinas/farmacologia , Análise de Variância , Animais , Comportamento Animal , Comportamento de Escolha/efeitos dos fármacos , Clozapina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Microdiálise , Testes Neuropsicológicos , Estimulação Luminosa , Ratos , Ratos Sprague-Dawley , Tempo de ReaçãoRESUMO
RATIONALE: Disruption in cognition is characteristic of psychiatric illnesses such as schizophrenia. Studies of drugs that improve cognition might provide a better insight into the mechanisms underlying cognitive deficits. OBJECTIVES: We compared the effects of the antipsychotic drugs aripiprazole, olanzapine, and haloperidol on performance deficit in a test of divided and sustained visual attention, the five-choice serial reaction time task (5-CSRTT), which provides information on attentional functioning (accuracy of visual discrimination), response control (measured by anticipatory and perseverative responses) and speed. METHODS: The cognitive deficit was induced by infusion of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the rat medial prefrontal cortex (mPFC). In vivo microdialysis was used to compare the effects of aripiprazole, olanzapine and haloperidol on CPP-induced glutamate (GLU) and serotonin (5-HT) release in the mPFC of conscious rats. RESULTS: Oral aripiprazole (1.0 and 3.0 mg/kg) and olanzapine (0.3 and 1.0 mg/kg), but not haloperidol (0.1 mg/kg), abolished the CPP-induced accuracy deficit and GLU release. Haloperidol and aripiprazole, but not olanzapine, reduced perseverative over-responding, while anticipatory responding was best controlled by olanzapine. However, these effects were not associated with changes in GLU release. No association was found between the effects of these antipsychotics on CPP-induced attentional performance deficits in the 5-CSRTT and 5-HT efflux. CONCLUSIONS: The data confirm that excessive GLU release in the mPFC is associated with attentional deficits. Thus, suppression of GLU release may be a target for the development of novel antipsychotic drugs with greater effect on some aspects of cognitive deficits.
Assuntos
Antipsicóticos/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Ácido Glutâmico/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/complicações , Análise de Variância , Animais , Antipsicóticos/uso terapêutico , Aripiprazol , Comportamento Animal , Benzodiazepinas/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/toxicidade , Haloperidol/farmacologia , Comportamento Impulsivo/tratamento farmacológico , Masculino , Microdiálise/métodos , Testes Neuropsicológicos , Olanzapina , Piperazinas/farmacologia , Piperazinas/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Quinolonas/farmacologia , Ratos , Tempo de Reação/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Serotonina/metabolismo , Fatores de TempoRESUMO
The cyclic-adenosine monophosphate response element-binding protein (CREB) family of transcription factors has been implicated in numerous forms of behavioral plasticity. We investigated CREB phosphorylation along some nodes of corticostriatal circuitry such as frontal cortex (FC) and dorsal (caudate-putamen, CPu) and ventral (nucleus accumbens, NAC) striatum in response to the contingent or non-contingent performance of the five-choice serial reaction time task (5-CSRTT) used to assess visuospatial attention. Three experimental manipulations were used; an attentional performance group (contingent, "master"), a group trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished (non-contingent, "yoked") and a control group matched for food deprivation and exposure to the test apparatus (untrained). Rats trained on the 5-CSRTT (both master and yoked) had higher levels of CREB protein in the FC, CPu, and NAC compared to untrained controls. Despite the divergent behavior of "master" and "yoked" rats CREB activity in the FC was not substantially different. In rats performing the 5-CSRTT ("master"), CREB activity was completely abolished in the CPu whereas in the NAC it remained unchanged. In contrast, CREB phosphorylation in CPu and NAC increased only when the contingency changed from goal-dependent to goal-independent reinforcement ("yoked"). The present results indicate that up-regulation of CREB protein expression across cortical and striatal regions possibly reflects the extensive instrumental learning and performance whereas increased CREB activity in striatal regions may signal the unexpected change in the relationship between instrumental action and reinforcement.
RESUMO
Complex microenvironmental stimuli influence neural cell properties. To study this, we developed a three-dimensional (3-D) neural culture system, composed of different populations including neurons, astrocytes, and neural stem cells (NSCs). In particular, these last-mentioned cells represent a source potentially exploitable to test drugs, to study neurodevelopment and cell-therapies for neuroregenerations. On seeding on matrigel in a medium supplemented with serum and mitogens, cells obtained from human fetal brain tissue formed 3-D self-organizing neural architectures. Immunocytochemical analysis demonstrated the presence of undifferentiated nestin+ and CD133+ cells, surrounded by ß-tub-III+ and GFAP+ cells, suggesting the formation of niches containing potential human NSCs (hNSCs). The presence of hNSCs was confirmed by both neurosphere assay and RT-PCR, and their multipotentiality was demonstrated by both immunofluorescent staining and RT-PCR. Flow cytometry analysis revealed that neurosphere forming cells originating from at least two different subsets expressing, respectively, CD133 and CD146 markers were endowed with different proliferative and differentiation potential. Our data implicate that the complexity of environment within niches and aggregates of heterogeneous neural cell subsets may represent an innovative platform for neurobiological and neurodevelopmental investigations and a reservoir for a rapid expansion of hNSCs.