RESUMO
Histamine H3 receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H3 receptor antagonist/inverse agonist: [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H3 receptors. Enerisant showed antagonist activity in vivo, as assessed using R-α-methylhistamine (a histamine H3 receptor agonist)-induced dipsogenia, and occupied the histamine H3 receptor in the frontal cortex in a dose-dependent manner. Enerisant also enhanced the extracellular levels of histamine in the posterior hypothalamus and the levels of dopamine and acetylcholine in the medial prefrontal cortex of rats. Enerisant exerted a procognitive effect or reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test in rats at doses at which less than 50% of the histamine H3 receptor were occupied (0.03-0.3 mg/kg, p.o.). In contrast, higher doses (3-10 mg/kg, p.o.) at which nearly all the histamine H3 receptors were occupied were needed to exert wake-promoting effects in rats. These results indicate that enerisant is a potent and selective histamine H3 receptor antagonist/inverse agonist with the potential to promote arousal and procognition in rats. Moreover, the results also suggest that the histamine H3 receptor occupancy required to exert a pharmacological effect may vary depending on the domain that is being tested. SIGNIFICANCE STATEMENT: Enerisant is a novel histamine H3 receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents. Moreover, an in vivo receptor binding study revealed that the in vivo occupancy of the histamine H3 receptor required to exert the pharmacological effects of enerisant varied, and such variations in required occupancy should be taken into account when performing dose selection in clinical studies.
Assuntos
Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/metabolismo , Vigília/efeitos dos fármacos , Animais , Eletroencefalografia , Antagonistas dos Receptores Histamínicos/farmacocinética , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Neurotransmissores/metabolismo , RatosRESUMO
BACKGROUND: Negative symptoms of schizophrenia are poorly managed using the currently available antipsychotics. Previous studies indicate that agonists of the metabotropic glutamate (mGlu) 2/3 receptors may provide a novel approach for the treatment of schizophrenia. However, the effects of mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators have not yet been clearly elucidated in animal models of the negative symptoms of schizophrenia. Recently, we reported that the forced swimming test in rats treated with subchronic MK-801, an NMDA receptor antagonist, may be regarded as a useful test to evaluate the activities of drugs against the negative symptoms of schizophrenia. METHODS: We evaluated the effects of LY379268, an mGlu2/3 receptor agonist, and BINA, an mGlu2 receptor positive allosteric modulator, on the hyperlocomotion induced by acute administration of MK-801 (0.15mg/kg, sc) and on the increase in the immobility time in the forced swimming test induced by subchronic treatment with MK-801 (0.5mg/kg, sc, twice a day for 7 days) in rats. RESULTS: Both LY379268 (3mg/kg, sc) and BINA (100mg/kg, ip) attenuated the increase in the immobility time induced by subchronic treatment with MK-801 at the same doses at which they attenuated the MK-801-induced increase in locomotor activity, but had no effect on the immobility time in saline-treated rats. CONCLUSIONS: The present results suggest that stimulation of the mGlu2 receptor attenuates the increase in the immobility time in the forced swimming test elicited by subchronic administration of MK-801, and may be potentially useful for treatment of the negative symptoms of schizophrenia.
Assuntos
Maleato de Dizocilpina/farmacologia , Imobilização/fisiologia , Atividade Motora/fisiologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Natação/fisiologia , Aminoácidos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
RATIONALE: Since the hypofunction of the N-methyl-D-aspartate (NMDA) receptor is known to be involved in the pathophysiology of schizophrenia, the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophrenia. OBJECTIVES: We investigated the efficacy of a glycine transporter 1 (GlyT1) inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms, both of which are poorly managed by current antipsychotics. RESULTS: A newly synthesized GlyT1 inhibitor, 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (TASP0315003) significantly improved cognitive deficit induced by MK-801 in the object recognition test in rats. Likewise, TASP0315003 significantly improved MK-801 impaired cognition in the social recognition test in rats and also enhanced social memory in treatment-naïve rats. In addition, repeated phencyclidine (PCP) treatment reduced the social interaction of paired mice, which may reflect negative symptoms such as social withdrawal, and both acute and sub-chronic treatment with TASP0315003 reversed the reduction in social interaction induced by PCP. Moreover, TASP0315003 additionally exhibited an antidepressant effect in the forced swimming test in rats. In contrast, TASP0315003 did not affect spontaneous locomotor activity or rotarod performance and did not induce catalepsy, indicating that TASP0315003 does not cause sedation or motor dysfunction, which is sometimes observed with the use of current antipsychotics. CONCLUSIONS: These results suggest that GlyT1 inhibitors including TASP0315003 may be useful for the treatment of cognitive dysfunction and the negative symptoms of schizophrenia without having undesirable central nervous system side effects.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Memória/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/tratamento farmacológico , Comportamento Social , Animais , Antidepressivos/uso terapêutico , Antipsicóticos/farmacologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Glicina/metabolismo , Masculino , Camundongos , Fenciclidina , Ratos , Esquizofrenia/metabolismoRESUMO
Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) in rats. Furthermore, TASP0443294 reduced the ketamine-induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM) sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294.
Assuntos
Antipsicóticos/farmacologia , Imidazóis/farmacologia , Oxazóis/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Células Cultivadas , Modelos Animais de Doenças , Eletroencefalografia/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Masculino , Atividade Motora/efeitos dos fármacos , Oxazóis/administração & dosagem , Oxazóis/farmacocinética , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Sono REM/efeitos dos fármacos , Estimulação QuímicaRESUMO
Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed. In the present study, the effects of the positive modulation of the glycine site on the NMDA receptor were investigated in an animal model of negative symptoms of schizophrenia. The subchronic administration of MK-801 increased immobility in the forced swimming test in rats without affecting spontaneous locomotor activity. The increased immobility induced by MK-801 was attenuated by the atypical antipsychotic clozapine but not by either the typical antipsychotic haloperidol or the antidepressant imipramine, indicating that the increased immobility induced by subchronic treatment with MK-801 in the forced swimming test may represent a negative symptom of schizophrenia. Likewise, positive modulation of the glycine sites on the NMDA receptor using an agonist for the glycine site, D-serine, and a glycine transporter-1 inhibitor, N-[(3R)-3-([1,1'-biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine hydrochloride (NFPS), significantly reversed the increase in immobility in MK-801-treated rats without reducing the immobility time in vehicle-treated rats. The present results show that the stimulation of the NMDA receptor through the glycine site on the receptor either directly with D-serine or by blocking glycine transporter-1 attenuates the immobility elicited by the subchronic administration of MK-801 and may be potentially useful for the treatment of negative symptoms of schizophrenia.
Assuntos
Maleato de Dizocilpina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Serina/metabolismo , Animais , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Clozapina/farmacologia , Modelos Animais de Doenças , Haloperidol/farmacologia , Imipramina/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Esquizofrenia/tratamento farmacológico , NataçãoRESUMO
Excess glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, and the activation of metabotropic glutamate 2 (mGlu2) receptor may exert antipsychotic effects by normalizing glutamate transmission. In the present study, we investigated the neurophysiologic and antipsychotic profiles of TASP0433864 [(2S)-2-[(4-tert-butylphenoxy)methyl]-5-methyl-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide], a newly synthesized positive allosteric modulator (PAM) of mGlu2 receptor. TASP0433864 exhibited PAM activity at human and rat mGlu2 receptors with EC50 values of 199 and 206 nM, respectively, without exerting agonist activity at rat mGlu2 receptor. TASP0433864 produced a leftward and upward shift in the concentration-response curve of glutamate-increased guanosine 5'-O-(3-[(35)S]thio)triphosphate binding to mGlu2 receptor. In contrast, TASP0433864 had negligible activities for other mGlu receptors, including mGlu3 receptor, and did not have any affinity for other receptors or transporters. In hippocampal slices, TASP0433864 potentiated an inhibitory effect of DCG-IV [(2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine], a mGlu2/3 receptor agonist, on the field excitatory postsynaptic potentials in the dentate gyrus, indicating that TASP0433864 potentiates the mGlu2 receptor-mediated presynaptic inhibition of glutamate release. Moreover, TASP0433864 inhibited both MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate]- and ketamine-increased cortical γ band oscillation in the rat cortical electroencephalogram, which have been considered to reflect the excess activation of cortical pyramidal neurons. The inhibitory effect of TASP0433864 on cortical activation was also observed in the mouse 2-deoxy-glucose uptake study. In a behavioral study, TASP0433864 significantly inhibited both ketamine- and methamphetamine-increased locomotor activities in mice and rats, respectively. Collectively, these findings indicate that TASP0433864 is a selective mGlu2 receptor PAM with antipsychotic activity, and the attenuation of excess glutamatergic neurotransmission may be involved in the action of TASP0433864.
Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Oxazóis/química , Oxazóis/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Técnicas de Cultura de Órgãos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this model. In the present study, the effects of adrenergic α2 receptor stimulation, which has been an effective treatment for ADHD, on attention/cognition performance were investigated in this model. Moreover, neuronal mechanisms mediated through adrenergic α2 receptors were investigated. We evaluated the effects of both clonidine, a non-selective adrenergic α2 receptor agonist, and guanfacine, a selective adrenergic α2A receptor agonist, using a 5-trial inhibitory avoidance test with SHR pups. Juvenile SHR exhibited a shorter transfer latency, compared with juvenile Wistar Kyoto (WKY) rats. Both clonidine and guanfacine significantly prolonged the transfer latency of juvenile SHR. The effects of clonidine and guanfacine were significantly blocked by pretreatment with an adrenergic α2A receptor antagonist. In contrast, the effect of clonidine was not attenuated by pretreatment with an adrenergic α2B receptor antagonist, or an adrenergic α2C receptor antagonist, while it was attenuated by a non-selective adrenergic α2 receptor antagonist. Furthermore, the effects of neither clonidine nor guanfacine were blocked by pretreatment with a selective noradrenergic neurotoxin. These results suggest that the stimulation of the adrenergic α2A receptor improves the attention/cognition performance of juvenile SHR in the 5-trial inhibitory avoidance test and that postsynaptic, rather than presynaptic, adrenergic α2A receptor is involved in this effect.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Animais , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Aprendizagem da Esquiva/efeitos dos fármacos , Clonidina/farmacologia , Modelos Animais de Doenças , Guanfacina/farmacologia , Inibição Psicológica , Masculino , Testes Neuropsicológicos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Resultado do TratamentoRESUMO
Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30-80 Hz) power. MK-801 (0.05-0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose-response curve; at higher doses (0.3-1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130-180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5-4 Hz) power at higher doses. PCP (1.25-10 mg/kg) and ketamine (2.5-30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10-30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1-10 mg/kg) and DOI (0.5-2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition.
Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ritmo Gama/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Anfetaminas/farmacologia , Animais , Encéfalo/fisiologia , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Eletrodos Implantados , Eletroencefalografia , Ritmo Gama/fisiologia , Ketamina/farmacologia , Masculino , Memantina/farmacologia , Metanfetamina/farmacologia , Fenciclidina/farmacologia , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Abnormalities in electroencephalogram gamma oscillations have been implicated in schizophrenic symptoms. N-methyl-d-aspartate (NMDA) receptor antagonists produce behavioral abnormalities that are similar to the symptoms of schizophrenia, including social and cognitive impairment, and also increase the power of spontaneous gamma oscillations in the frontal cortex in rodents. Both mGlu2/3 receptor agonists and mGlu1 receptor antagonists reportedly improve behavioral abnormalities elicited by NMDA receptor antagonists in rodents. The present study evaluated the effects of an mGlu2/3 receptor agonist and an mGlu1 receptor antagonist on aberrant basal gamma oscillations elicited by an NMDA receptor antagonist, ketamine, in the rat frontal cortex. Ketamine increased spontaneous cortical gamma oscillations. Pretreatment with an mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1 receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), reduced the ketamine-induced basal gamma hyperactivity. These findings indicate that the stimulation of mGlu2/3 receptors and the inhibition of mGlu1 receptors reverse aberrant gamma oscillations, and these effects may partially explain the antipsychotic-like properties of mGlu2/3 receptor agonists and mGlu1 receptor antagonists.
Assuntos
Lobo Frontal/efeitos dos fármacos , Ketamina/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Aminoácidos/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Eletroencefalografia , Lobo Frontal/fisiologia , Masculino , Quinolinas/farmacologia , Ratos Sprague-DawleyRESUMO
Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. Both the stimulation of the metabotropic glutamate (mGlu) 2/3 receptor and the blockade of the mGlu1 receptor have been shown to be effective in a number of animal models of schizophrenia. However, the efficacy for social cognition, which is poorly managed by current medication, has not been fully addressed. The present study evaluated the effects of an mGlu2/3-receptor agonist and an mGlu1-receptor antagonist on social memory impairment in rats. Pretreatment with an mGlu2/3-receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1-receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) without affecting the social interactions. In addition, the intraperitoneal administration of an mGlu2-receptor potentiator, 3'-[[(2-cyclopentyl-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-5-yl)oxy]methyl]-[1,1'-biphenyl]-4-carboxylic acid (BINA), also improved the MK-801-induced impairment of social memory, which was blocked by pretreatment with an mGlu2/3-receptor antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). These findings indicate that both the stimulation of the mGlu2 receptor and the inhibition of an mGlu1 receptor improve social memory impairment elicited by MK-801, and both manipulations could be effective approaches for the treatment of certain cognitive dysfunctions observed in schizophrenic patients.
Assuntos
Transtornos da Memória/tratamento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Maleato de Dizocilpina/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Xantenos/farmacologia , Xantenos/uso terapêuticoRESUMO
The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in the regulation of dopamine release by the metabotropic glutamate (mGlu) 2/3 receptors in the nucleus accumbens (NAc) shell was investigated using an in vivo microdialysis evaluation. The local application of 10 microM of LY341495, an mGlu 2/3 receptor antagonist, significantly increased extracellular dopamine levels in the NAc shell in freely moving rats. Pretreatment with an AMPA receptor antagonist, NBQX (0.3 mg/kg, i.p.) significantly attenuated the increase in dopamine release induced by LY341495 application to the basal level, while the systemic administration of NBQX alone had no effect on dopamine release in this region of the brain. Moreover, the local application of an AMPA receptor potentiator, CX546, at 100 or 300 microM also enhanced dopamine release in the NAc shell in a concentration-dependent manner. These findings suggest that the activation of the postsynaptic AMPA receptor plays a role in mediating the regulation of dopamine release by the mGlu 2/3 receptor in the NAc shell.
Assuntos
Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Receptores de AMPA/fisiologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Aminoácidos/farmacologia , Animais , Dioxóis/farmacologia , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Microdiálise , Núcleo Accumbens/efeitos dos fármacos , Piperidinas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , Xantenos/farmacologiaRESUMO
The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [(3)H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [(3)H]dopamine uptake in vitro. The rank order of potency was reserpine>>fluoxetine, paroxetine>fluvoxamine, methamphetamine>MDMA. Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine. Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine. These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Dopamina/metabolismo , Fluoxetina/farmacologia , Fluvoxamina/farmacologia , Haloperidol/farmacologia , Masculino , Metanfetamina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Paroxetina/farmacologia , Ratos , Ratos Wistar , Reserpina/farmacologia , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismoRESUMO
Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.
Assuntos
Clozapina/farmacologia , Transtornos Cognitivos/metabolismo , Nootrópicos/farmacologia , Reconhecimento Psicológico/fisiologia , Sarcosina/análogos & derivados , Serina/farmacologia , Análise de Variância , Animais , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/tratamento farmacológico , Maleato de Dizocilpina , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Haloperidol/farmacologia , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Sarcosina/farmacologia , Serina/metabolismo , Estatísticas não ParamétricasRESUMO
(1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a potent and selective metabotropic glutamate 2/3 (mGlu 2/3) receptor antagonist, exhibits antidepressant-like activities in some animal models. In the present study, we examined the effect of MGS0039 on extracellular dopamine levels in the rat nucleus accumbens (NAc) shell using in vivo microdialysis evaluation because accumbal dopamine has been implicated in depression. Local application of MGS0039 into the NAc shell at 10 microM significantly increased extracellular dopamine levels in the NAc shell in freely moving rats. In contrast, local application of 10 microM of LY354740, an mGlu 2/3 receptor agonist, significantly decreased extracellular dopamine levels in the same brain region. These findings suggest that dopamine release in the NAc shell is regulated by mGlu 2/3 receptors, and that the effect on dopamine levels in the NAc shell may partially explain the antidepressant-like properties of mGlu 2/3 receptor antagonists.
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Ácidos Dicarboxílicos/farmacologia , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Análise de Variância , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Masculino , Microdiálise/métodos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
(1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a selective group II metabotropic glutamate receptor (mGluR) antagonist, exhibits antidepressant-like activities in rodent models. In the present studies, to clarify the involvement of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in exhibition of the antidepressant-like properties of MGS0039, we examined the effect of an AMPA receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), on the antidepressant-like effect of MGS0039 in the mouse tail suspension test. We also examined the effects of NBQX on increased serotonin release after treatment with MGS0039 in the rat medial prefrontal cortex (mPFC) using in vivo microdialysis evaluation. In the tail suspension test, MGS0039 (0.3-3 mg/kg, i.p.) treatment dose-dependently and significantly reduced immobility time. Pretreatment with NBQX (10 mg/kg, s.c.) significantly prevented the antidepressant-like effect of MGS0039 in the tail suspension test, while NBQX itself had no effect on immobility time. In the microdialysis evaluation, administration of MGS0039 (10 mg/kg, i.p.) significantly increased serotonin levels in mPFC in freely moving rats, while NBQX (1 mg/kg, i.p.) itself had no effect on serotonin release in this region. Pretreatment with NBQX significantly attenuated the increase in serotonin release by MGS0039. These findings suggest that stimulation of postsynaptic AMPA receptors plays a role in mediating the pharmacological effects of MGS0039.
Assuntos
Antidepressivos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Ácidos Dicarboxílicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de AMPA/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Análise de Variância , Animais , Antidepressivos de Segunda Geração/farmacologia , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Fluvoxamina/farmacologia , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microdiálise , Córtex Pré-Frontal/química , Córtex Pré-Frontal/efeitos dos fármacos , Quinoxalinas/farmacologia , Ratos , Serotonina/análiseRESUMO
Glutamatergic abnormalities play roles in several psychiatric disorders. Glutamate acts at two classes of receptors, ionotropic and metabotropic glutamate receptors (mGluR), the latter is classified into three group, based on receptor homology and signaling mechanisms. Among them, recent pharmacological and histochemical studies suggest that the group II mGluR (mGluR2 and mGluR3) plays crucial roles in the control of emotional states. We previously reported that MGS0039, a selective group II mGluR antagonist, exhibited dose-dependent antidepressant-like effects in some animal models. However, the mechanism by which group II mGluR antagonists exhibit such effects is still unclear. In the present two studies, we examined neuropharmacological effects of group II mGluR antagonists on monoaminergic neurons. In an electrophysiological study, MGS0039 dose-dependently and significantly increased the firing rate of dorsal raphe nucleus (DRN) serotonergic neurons. LY341495, another group II mGluR antagonist, also increased DRN serotonergic neural activity significantly. Consistent with the findings of this electrophysiological study, MGS0039 significantly increased extracellular level of serotonin in rat medial prefrontal cortex in a microdialysis study. In contrast, MGS0039 had no effect on the activity of locus coeruleus noradrenergic neurons. These findings suggest that modulation of serotonergic neuron might be, at least in part, responsible for the antidepressant-like effects of group II mGluR antagonists.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Locus Cerúleo/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Aminoácidos/farmacologia , Animais , Antidepressivos/farmacologia , Monoaminas Biogênicas/metabolismo , Compostos Bicíclicos com Pontes/farmacologia , Ácidos Dicarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Locus Cerúleo/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/metabolismo , Serotonina/metabolismo , Xantenos/farmacologiaRESUMO
(R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Fenazocina/análogos & derivados , Pirrolidinas/farmacologia , Receptores sigma/efeitos dos fármacos , Sulpirida/análogos & derivados , Tartaratos/farmacologia , Amissulprida , Animais , Apomorfina/antagonistas & inibidores , Apomorfina/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/psicologia , Agonistas de Dopamina/farmacologia , Interações Medicamentosas , Feminino , Haloperidol/farmacologia , Masculino , Camundongos , Nootrópicos/farmacologia , Fenazocina/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Antagonistas da Serotonina/farmacologia , Sulpirida/farmacologia , Receptor Sigma-1RESUMO
MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate) is a antipsychotic agent that binds to sigma-1 receptor. MS-377 showed anti-dopaminergic and anti-serotonergic activities and antagonistic action against phencyclidine (PCP)-induced behaviors in an animal model. These anti-psychotic activities of MS-377 are attributable to association with sigma-1 receptor. However, the mechanism by which the sigma-1 receptor ligands exact those numerous effects remains to be elucidated. In the present study, we evaluated the effect of MS-377 on N-methyl-D-aspartate (NMDA) receptor ion-channel complex in primary cultured rat neuronal cells. First, we examined the effect of MS-377 on NMDA-induced Ca2+ influx with fura-2/ AM loaded cells. MS-377 showed no effects on the basal Ca2+ concentration and NMDA-induced Ca2+ influx by itself PCP and SKF-10047 reduced the NMDA-induced increase in intracellular Ca2+ concentration. Pre-incubation of 1 microM MS-377 was found to significantly block the reduction by PCP or SKF-10047 of the NMDA-induced Ca2+ influx. Second, the effect of MS-377 on [3H]MK-801 intact cell binding was examined. PCP, haloperidol and (+)-pentazocine inhibited [3H]MK-801 binding, although MS-377 showed no effect by itself Pre-treatment of MS-377 markedly reversed the inhibition of [3H]MK-801 binding by PCP in a dose-dependent manner. These effects of MS-377 may depend on its affinity for the sigma-1 receptor, because MS-377 is a selective sigma-1 receptor ligand without any affinity for NMDA receptor ion-channel complex. These observations suggest that the MS-377 indirectly modulated the NMDA receptor ion-channel complex, and the anti-psychotic activities of MS-377, in part, are attributable to such on action via sigma-1 receptor.