RESUMEN
RATIONALE: Substances acting as agonists of group II mGlu receptors with joint group I mGlu receptor antagonist effects, or group II mGlu receptors agonists, were shown to induce antianxiety-like effect in rats after intrahippocampal administration. OBJECTIVE: The present study was undertaken to establish whether a more selective group I, II, III mGlu receptors agonists/antagonists induce anxiolytic-like effects after injection to the hippocampus. METHODS: (S)-4-Carboxyphenylglycine [(S)-4CPG] and 7-(hydroxyimino)cyclopropan[b]chromen-1alpha-carboxylic ethyl ester (CPCCOEt), selective antagonists at group I mGlu receptors, or (+)1S, 2S, 5R, 6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), two selective agonists of group II mGlu receptors, as well as (1S, 2S, 4S, 5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I (ABHxD-I), an agonist at all three groups of mGlu receptors and L-serine-O-phosphate (L-SOP), an agonist at group III mGlu receptors, were used. All compounds were administered into the CA1 region of the dorsal hippocampus. The conflict drinking Vogel test in rats was used to estimate the anxiolytic-like effects of all the compounds. RESULTS: After intrahippocampal administration, both selective group I mGlu receptors antagonists (S)-4CPG and CPCCOEt, as well as the selective agonists of group II mGlu receptors LY 354740 and L-CCG-I, and an agonist of group III mGlu receptors, L-SOP, induced anticonflict effects. CONCLUSION: Selective antagonists of group I mGlu receptors and agonists of group II and group III mGlu receptors exhibit anxiolytic-like activity in the conflict drinking test. It seems that the hippocampus may be one of the brain structures involved in the anticonflict effect of mGlu receptor agonists/antagonists.
Asunto(s)
Ansiolíticos/farmacología , Hipocampo/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Masculino , Ratas , Ratas WistarRESUMEN
The effects of zinc, the N-methyl-D-aspartate glutamate receptor inhibitor, were studied in mice and rats using the forced swim test. Zinc (ZnSO4) in a dose of 30 mg/kg and imipramine (30 mg/kg), reduced the immobility time in the forced swim test in both species. Moreover, combined treatment in this test with zinc and imipramine at their ineffective doses (1 and 5 mg/kg, respectively) induced a statistically significant effect in rats. The doses active in the forced swim test reduced (in mice) or did not affect (in rats) locomotor activity. The results obtained indicate that zinc induces an antidepressant-like effect and enhances the effect of imipramine in the forced swim test, suggesting a potential antidepressant activity of zinc in humans.
Asunto(s)
Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Interacciones Farmacológicas/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estrés Fisiológico/tratamiento farmacológico , Zinc/farmacología , Animales , Antidepresivos Tricíclicos/farmacología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Depresión/metabolismo , Depresión/fisiopatología , Relación Dosis-Respuesta a Droga , Imipramina/farmacología , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Fisiológico/metabolismo , Estrés Fisiológico/fisiopatología , NataciónRESUMEN
Physiological functions of glutamic acid, the major neurotransmitter in the central nervous system, are mediated by the two receptor families: ionotropic glutamate receptors (iGluRs), and metabotropic glutamate receptors (mGluRs). Eight mGluR subtypes (mGluR1-mGluR8), together with splice variants, have been identified and classified into three groups. One of the features of mGluRs is their profile of functional expression throughout postnatal development. Several lines of evidence suggest age-dependent differences in the pattern or amount of mGluR-mediated phosphatidylinositol (P1) turnover as well as in the expression of mGluRs. The aim of the present study was to investigate how the different effects of mGluR agonists on cAMP accumulation change during rat postnatal life. We have found that the stimulatory effect of glutamate and/or 1S,3R-ACPD on cAMP accumulation predominates in young animals and decreases in the adults. We have also shown that the enhancement of the effect of noradrenaline on cAMP accumulation by 1S,3R-ACPD in rats is an age-dependent phenomenon which reaches its maximum in 14-30-day-old rats and gradually decreases during their maturation. On the basis of our studies, we conclude that the activation of mGluRs resulting in cAMP accumulation depends on the age of an animal.
Asunto(s)
Envejecimiento/metabolismo , Corteza Cerebral/metabolismo , AMP Cíclico/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Adenosina Desaminasa/farmacología , Animales , Colforsina/farmacología , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Ácido Glutámico/farmacología , Técnicas In Vitro , Masculino , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistas , Estimulación QuímicaRESUMEN
Using the conflict drinking Vogel test in rats as a model we examined the anxiolytic-like activity of (S)-4-carboxyphenylglycine (S-4CPG), an antagonist of group I metabotropic glutamate receptors (mGlu receptors), of (RS)-a-methylserine-O-phosphate-monophenyl ester (MSOPPE), an antagonist of group II mGlu receptors, and of (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), an agonist of group II mGlu receptors. The obtained results indicate that intrahippocampal administration of S-4CPG and L-CCG-I, but not MSOPPE to rats produces a dose-dependent anticonflict effect, which is unrelated to the reduced perception of the stimulus or to an increased thirst drive. The hippocampus may be one of the neuroanatomical sites of the anxiolytic-like effects of either agent.
Asunto(s)
Ansiolíticos/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Animales , Conducta Animal , Benzoatos/farmacología , Conflicto Psicológico , Conducta de Ingestión de Líquido , Glicina/análogos & derivados , Glicina/farmacología , Masculino , Fosfoserina/farmacología , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidoresRESUMEN
Evidence suggests that metabotropic glutamate receptors (mGluR) are involved in mediating seizures and epileptogenesis. In the present experiments, the selective, group II mGluR agonist (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid (LY354740, 0.1-1.0 microM) inhibited spontaneous epileptiform discharges which developed in rat cortical slices in Mg2+-free medium. LY354740 (4-16 mg/kg) administered prior to an injection of pentylenetetrazol (80 mg/kg) or picrotoxin (3.2 mg/kg) produced a dose-dependent decrease in the number of mice exhibiting clonic convulsions, but had no effect on N-methyl-D-aspartate (NMDA, 150 mg/kg)-induced convulsions. LY354740 (4-16 mg/kg) did not affect lethality induced in mice by pentylenetetrazol, picrotoxin or NMDA. LY354740 potentiated the anticonvulsant activity of the conventional antiepileptic drug diazepam, significantly decreasing the ED50 for that drug's effect on pentylenetetrazol-induced convulsions by 30%, but had no influence on anticonvulsant activity of ethosuximide and valproic acid. A pharmacokinetic interaction between LY354740 and diazepam, leading to the lowering of the plasma level of free diazepam, was also demonstrated. Our data suggest that the group II mGluR agonist LY354740 possesses anti-seizure activity and may modify the effects of some conventional antiepileptic drugs.
Asunto(s)
Ansiolíticos/uso terapéutico , Compuestos Bicíclicos con Puentes/uso terapéutico , Convulsivantes/antagonistas & inhibidores , Pentilenotetrazol/antagonistas & inhibidores , Picrotoxina/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/agonistas , Convulsiones/tratamiento farmacológico , Análisis de Varianza , Animales , Ansiolíticos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Compuestos Bicíclicos con Puentes/farmacología , Convulsivantes/toxicidad , Diazepam/sangre , Diazepam/farmacocinética , Diazepam/uso terapéutico , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Electrofisiología , Masculino , Ratones , N-Metilaspartato , Ratas , Ratas Wistar , Convulsiones/inducido químicamenteRESUMEN
The effects of zinc, the NMDA receptor inhibitor, were studied in the forced swimming (Porsolt's) test in mice. Zinc (ZnSO4) at a dose of 30 mg/kg (but not at a dose of 10 mg/kg), similarly to imipramine (30 mg/kg), reduced the immobility time in that test. Moreover, zinc at both doses reduced the locomotor activity. The obtained results indicate that zinc induces an antidepressant-like effect in the forced swimming test. Since zinc reduces the locomotor activity, this antidepressant-like effect is not related to the alteration of general activity.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Natación/psicología , Zinc/farmacología , Animales , Antidepresivos Tricíclicos/farmacología , Depresión/psicología , Relación Dosis-Respuesta a Droga , Imipramina/farmacología , Ratones , Actividad Motora/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
The mechanism of adenylyl cyclase activation by the stimulation of metabotropic glutamate receptors (mGluRs) is still unknown. Our previous studies have shown that mGluR agonist, ibotenic acid, produced a significant increase in cAMP accumulation. The aim of the present studies was to investigate the mechanism of ibotenate-stimulated cAMP formation in cortical slices of adult rats. Antagonists of all groups of mGluRs were examined to establish their effects on the stimulation of cAMP production by ibotenic acid. The obtained results indicate that ibotenate-stimulated cAMP accumulation in the rat brain cortical slices depends on the activation of mGluR1, but not on mGluR5. Moreover, activation of group II and group III mGluRs also influences ibotenate-stimulated cAMP formation.
Asunto(s)
Corteza Cerebral/metabolismo , AMP Cíclico/biosíntesis , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Iboténico/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Adenina/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Masculino , Piridinas/farmacología , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/antagonistas & inhibidoresRESUMEN
CaM-KII exhibits broad distribution within neurons and discrete localization inside the cell, and it is highly abundant in the postsynaptic densities. The aim of the present study was to investigate the influence of chronic imipramine administration on the CaM-KII activity in postsynaptic densities and synaptosomal plasma membrane fraction isolated from the rat frontal cortex and hippocampus. In the present study, we showed that chronic imipramine administration did not affect the CaM-KII activity localized postsynaptically. Moreover, our results indicated that chronic imipramine treatment evoked a large (300%) increase in CaM-KII activity in synaptosomal plasma membranes fraction isolated from frontal cortex.