RESUMEN
Earlier studies have demonstrated that the agonists of the mGlu(2/3) receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu(2/3) receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1-5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu(2) receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5-5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABA(A) receptor antagonist flumazenil (10mg/kg) or GABA(B) receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT(1A) receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT(2A/2C) receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABA(A) receptors, presynaptic 5-HT(1A) and postsynaptic 5-HT(2A/2C) receptors is responsible for the phenomenon. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Asunto(s)
Aminoácidos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Agonistas de Aminoácidos Excitadores/uso terapéutico , Fiebre/tratamiento farmacológico , Piridinas/uso terapéutico , Receptores AMPA/metabolismo , Sulfonamidas/uso terapéutico , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fiebre/etiología , Flumazenil/uso terapéutico , Antagonistas del GABA/uso terapéutico , Moduladores del GABA/uso terapéutico , Masculino , Ratones , Ácidos Fosfínicos/uso terapéutico , Piperazinas/uso terapéutico , Propanolaminas/uso terapéutico , Ritanserina/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Aislamiento Social , Estrés Psicológico/complicacionesRESUMEN
BACKGROUND AND PURPOSE: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied. EXPERIMENTAL APPROACH: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed. KEY RESULTS: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs. CONCLUSION AND IMPLICATIONS: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis.
Asunto(s)
Conducta Animal/efectos de los fármacos , Ciclopentanos/uso terapéutico , Agonistas de Receptores GABA-B/uso terapéutico , Ácidos Fosfínicos/uso terapéutico , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Pirimidinas/uso terapéutico , Receptores de GABA-B/metabolismo , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Catalepsia/inducido químicamente , Ciclopentanos/administración & dosificación , Ciclopentanos/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Lóbulo Frontal/fisiopatología , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/efectos adversos , Antagonistas de Receptores de GABA-B/farmacología , Hipercinesia/tratamiento farmacológico , Hipercinesia/metabolismo , Hipercinesia/psicología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ácidos Fosfínicos/administración & dosificación , Ácidos Fosfínicos/efectos adversos , Psicosis Inducidas por Sustancias/metabolismo , Psicosis Inducidas por Sustancias/psicología , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Síndrome , Ácido gamma-Aminobutírico/administración & dosificación , Ácido gamma-Aminobutírico/efectos adversos , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
The contribution of (R)-enantiomer of N-methyl-salsolinol (1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; NMSal) to the degeneration of dopaminergic neurons in the course of Parkinson's disease (PD) has been predominantly suggested by in vitro experiments in cell culture and by an in vivo study in which this compound has been directly injected into the rat striatum. The aim of the present study was to examine the effects of racemic NMSal (50 and 100 mg/kg) administered systemically, acutely and chronically for 21 days to rats, on the neurochemical and behavioral markers of PD. Our results showed that racemic NMSal easily penetrated the blood-brain barrier. Its brain level was relatively high 2-6 h after a single injection than gradually decreased. NMSal was quickly eliminated from the rat brain, its concentration 24 h after withdrawal from chronic treatment was very low. NMSal at both examined doses did not affect striatal and nigral levels of dopamine (DA) 2 h after the first and last chronic injections, however, it markedly changed DA catabolism. In the striatum both its doses evoked a significant acceleration of the total and oxidative, monoamine oxidase (MAO)-dependent DA catabolism without affecting the catechol-O-methyltransferase (COMT)-dependent O-methylation. In the substantia nigra (SN), only the higher dose of NMSal produced such effect. DA catabolism in either structure was the same as in control 24 h after cessation of chronic treatment. The second characteristic marker of PD, the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SN, was not affected by chronic NMSal treatment as revealed by the stereological counting. In the behavioral study, it was found that racemic NMSal significantly suppressed spontaneous locomotor activity and effectively prevented that stimulated by apomorphine. Our results suggest that NMSal may play an important role in the regulation of dopaminergic activity rather than in inducing changes of parkinsonian type.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Sustancia Negra/efectos de los fármacos , Tetrahidroisoquinolinas/administración & dosificación , Anfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Inhibidores de Captación de Dopamina/farmacología , Esquema de Medicación , Interacciones Farmacológicas , Electromiografía , Masculino , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/ultraestructura , Actividad Motora/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/ultraestructura , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/fisiopatología , Sustancia Negra/fisiología , Tetrahidroisoquinolinas/metabolismo , Factores de Tiempo , Distribución Tisular , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND AND PURPOSE: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. EXPERIMENTAL APPROACH: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. KEY RESULTS: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. CONCLUSIONS AND IMPLICATIONS: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.
Asunto(s)
Antidepresivos/farmacología , Antagonistas de Receptores de GABA-B , Compuestos Organofosforados/farmacología , Ácidos Fosfínicos/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Imipramina/farmacología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de GABA-B/metabolismo , Estrés Psicológico/fisiopatología , Sacarosa/administración & dosificación , Sacarosa/farmacología , Natación , TritioRESUMEN
A deficiency of the dopaminergic transmission in the mesocortical system has been suggested to contribute to cognitive disturbances in Parkinson's disease. Therefore, the aim of the present study was to examine whether the long-term administration of a commonly used herbicide, paraquat, which has already been found to induce a slowly progressing degeneration of the nigrostriatal neurons, influences mesocortical dopaminergic neurons in rats. Paraquat at a dose of 10 mg/kg i.p. was injected either acutely or once a week for 4, 8, 12 and 24 weeks. Acute treatment with this pesticide increased the level of homovanillic acid (HVA) and HVA/dopamine ratio in the prefrontal cortex. After 8 weeks of administration paraquat increased the number of stereologically counted tyrosine hydroxylase-immunoreactive (TH-ir) neurons and their staining intensity in the ventral tegmental area (VTA), which is a source of the mesocortical dopaminergic projection. At the same time, few TH-ir neurons appeared in different regions of the cerebral cortex: in the frontal, cingulate, retrosplenial and parietal cortices. Chronic paraquat administration did not influence the level of dopamine in the prefrontal cortex but increased the levels of its metabolites: 3,4-dihydroxyphenylacetic acid (after 8-12 weeks), HVA (after 4 and 12 weeks) and HVA/dopamine ratio (4 weeks). After 24 weeks this pesticide reduced the number of TH-ir neurons in the VTA by 42% and of the Nissl-stained neurons by 26%, and induced shrinkage of this structure by ca. 25%. Moreover, TH-ir neurons in the cortex were no more visible after such a long period of administration and levels of dopamine metabolites returned to control values. The present results suggest that the long-term paraquat administration destroys dopaminergic neurons of the VTA. However, compensatory activation of the VTA neurons and cortex overcomes progressing degeneration and maintains cortical dopaminergic transmission.
Asunto(s)
Corteza Cerebral/citología , Dopamina/metabolismo , Herbicidas/administración & dosificación , Degeneración Nerviosa/inducido químicamente , Neuronas/efectos de los fármacos , Paraquat/administración & dosificación , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Modelos Animales de Enfermedad , Ácido Homovanílico/metabolismo , Inmunohistoquímica/métodos , Masculino , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
The study was conducted to determine whether the expression of behavioral supersensitivity induced by haloperidol (HAL) administered once daily (2 mg/kg i.p.) for 14 days is associated with the alterations in activity of neuropeptide Y (NPY) system in the striatum (caudate-putamen) and nucleus accumbens. Dopamine supersensitivity was tested by measurement of locomotor activity and stereotyped behavior after administration of the dopamine D2/D3 receptor agonist quinpirole (1 mg/kg i.p.) on day 1, 3 and 7 after HAL withdrawal. Neuropeptide Y-like immunoreactivity (NPY-LI) was determined in the striatum and nucleus accumbens isolated 6 h after quinpirole injection on day 1, 3 and 7 after the end of HAL treatment. NPY mRNA was quantified in these structures on day 7 after HAL withdrawal. HAL increased spontaneous locomotor activity and prevalence of rearing, grooming and head-down sniffing. At the same time, striatal NPY-LI increased progressively from the reduced level found on day 1 of haloperidol withdrawal. NPY mRNA remained unchanged. In saline-treated rats, quinpirole enhanced locomotion, rearing, and induced intense head-down sniffing and oral activity. These behavioral effects were accompanied by a decrease in striatal NPY-LI. NPY mRNA was slightly increased. HAL treatment altered response to quinpirole, namely it increased locomotion, intensified oral activity and reduced rearing and head-down sniffing. The second and the third quinpirole injection decreased NPY-LI levels. NPY mRNA was unchanged. In the nucleus accumbens, apart from a decrease in NPY-LI on day 1 after the last haloperidol dose, the level of NPY-LI and NPY mRNA in any experimental group did not differ from the control value. The presented results suggest that the alterations in the activity of the striatal but not nucleus accumbens NPY system contribute to adaptive changes induced by long-term haloperidol treatment and may be of significance to the motor hyperactivity induced by intermittent stimulation of postsynaptic dopamine D2 receptors.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Actividad Motora/efectos de los fármacos , Neuropéptido Y/metabolismo , Animales , Cuerpo Estriado/citología , Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Hibridación in Situ , Masculino , Neuropéptido Y/genética , Quinpirol/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
The aim of the present study was to examine the influence of the long-term paraquat administration on the dopaminergic nigrostriatal system in rats. Paraquat was injected at a dose of 10 mg/kg i.p. for 4-24 weeks. We found that this pesticide reduced the number of tyrosine hydroxylase-immunoreactive neurons of the substantia nigra; after the 4-week treatment the reduction (17%, nonsignificant) was confined to the rostrocentral region of this structure but, after 24 weeks, had spread along its whole length and was approximately 37%. Moreover, it induced a biphasic effect on dopaminergic transmission. First, levels of dopamine, its metabolites and turnover were elevated (4-8 weeks) in the caudate-putamen, then all these parameters returned to control values (12 weeks) and dropped by 25-30% after 24 weeks. The binding of [3H]GBR 12,935 to dopamine transporter in the caudate-putamen was decreased after 4-8 weeks, then returned to control values after 12 weeks but was again decreased after 24 weeks. Twenty-four-week paraquat administration also decreased the level of tyrosine hydroxylase (Western blot) in the caudate-putamen. In addition, paraquat activated serotonin and noradrenaline transmission during the first 12 weeks of treatment but no decreases in levels of these neurotransmitters were observed after 24 weeks. The above results seem to suggest that long-term paraquat administration produces a slowly progressing degeneration of nigrostriatal neurons, leading to delayed deficits in dopaminergic transmission, which may resemble early, presymptomatic, stages of Parkinson's disease.
Asunto(s)
Dopamina/fisiología , Herbicidas/toxicidad , Neuronas/patología , Paraquat/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Sustancia Negra/citología , Algoritmos , Animales , Autorradiografía , Núcleo Caudado/metabolismo , Dopamina/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neurotransmisores/metabolismo , Norepinefrina/metabolismo , Enfermedad de Parkinson Secundaria/metabolismo , Piperazinas/farmacología , Putamen/metabolismo , Ratas , Ratas Wistar , Serotonina/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Transmisión Sináptica/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
It was well established that compounds which decrease glutamatergic transmission via blockade of NMDA or group I mGlu receptors produce anxiolytic- and antidepressant-like action in animal tests and models. Since group III metabotropic glutamate receptor (mGluR) agonists are known to reduce glutamatergic neurotransmission by the inhibition of glutamate release, we decided to investigate potential anxiolytic- and/or antidepressant-like effects of group III mGluR agonists, after central administration in rats. It was found that group III mGluR agonists, (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) and 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (HomoAMPA), given intrahippocampally, produced a dose-dependent anxiolytic-like effect in the conflict drinking test. The effects of ACPT-I and HomoAMPA were reversed by (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), group III mGluR antagonist. Moreover, a dose-dependent antidepressant-like action of group III mGluR agonists, ACPT-I and (RS)-4-phosphonophenylglycine (RS-PPG), but not HomoAMPA, was found in behavioral despair test, after intracerebroventricular injections, and the effect of ACPT-I was reversed by CPPG. The results obtained indicate that group III mGluR agonists produce anxiolytic- as well as antidepressant-like effects in behavioral tests, after central administration in rats. The reduction of glutamate release by group III mGluR activation may be a possible mechanism underlying anxiolytic- and antidepressant-like properties of the tested compounds. In conclusion, the results of our studies indicate that group III mGlu receptor agonists may play a role in the therapy of both anxiety and depression.
Asunto(s)
Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Hipocampo/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/análogos & derivados , Animales , Ciclopentanos/administración & dosificación , Hipocampo/fisiología , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/fisiología , Ácidos Tricarboxílicos/administración & dosificación , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificaciónRESUMEN
Using the olfactory bulbectomy model of depression, we examined the antidepressant-like activity of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in rats. Bulbectomized rats required a significantly greater number of trials to acquire the response similar to sham-operated controls in the passive avoidance model. Both the prolonged (but not acute) treatment with MPEP and with antidepressant drug-desipramine restored the learning deficit. The results indicate that the prolonged blockade of mGlu5 receptors exerts antidepressant-like effects in rats.
Asunto(s)
Antidepresivos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Aprendizaje/efectos de los fármacos , Bulbo Olfatorio/cirugía , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Antidepresivos/metabolismo , Antidepresivos Tricíclicos/metabolismo , Antidepresivos Tricíclicos/farmacología , Desipramina/metabolismo , Desipramina/farmacología , Antagonistas de Aminoácidos Excitadores/metabolismo , Humanos , Aprendizaje/fisiología , Masculino , Piridinas/metabolismo , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl-D-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.
Asunto(s)
Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Reacción de Prevención/efectos de los fármacos , Piridinas/administración & dosificación , Animales , Ansiedad/tratamiento farmacológico , Reacción de Prevención/fisiología , Depresión/tratamiento farmacológico , Masculino , Ratones , Ratas , Ratas WistarRESUMEN
Previous studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a subsensitivity of group I metabotropic glutamate receptors (mGluR) in hippocampus. In the present study effects of antidepressant treatment on the expression of mGluR1a and mGluR5a, belonging to the group I mGluR, were investigated in rat brain hippocampus using immunohistochemical and Western blot methods, respectively. Male Wistar rats were treated singly or chronically for 21 days with imipramine, 10 mg/kg, twice daily; with ECS (90 mA, 50 Hz, 0.5 s) every second day; or with haloperidol, 1.2 mg/kg, once daily. Appropriate controls were injected with saline. Rats were sacrificed 24 h after the last treatment and their hippocampi were taken out for analysis. It was found that the mGluR1a-immunoreactivity expression increased significantly in Ammon's horn (CA) regions after chronic ECS. The most pronounced effect was observed in the CA3. No significant effects were found after single treatment or after haloperidol. The expression of mGluR5a increased significantly after chronic imipramine in the CA1 and after chronic ECS in the CA3 region. The results obtained indicate an influence of antidepressant treatment on group I mGluR. This increase in the receptor protein level may be a compensatory mechanism developing after chronic treatment.
Asunto(s)
Electrochoque , Hipocampo/efectos de los fármacos , Imipramina/administración & dosificación , Receptores de Glutamato Metabotrópico/biosíntesis , Animales , Esquema de Medicación , Electrochoque/estadística & datos numéricos , Hipocampo/química , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/análisisRESUMEN
Excitatory neurotransmitter glutamate, as well as corticoliberin (CRF) and neuropeptide Y (NPY) play an important role in fear and anxiety. Among the brain structures engaged in these effects the important one is amygdala. In the present study, a single and double immunohistochemical staining techniques were used in order to visualize CRF, NPY and metabotropic glutamate receptors (mGluR1a) in rat amygdala. MGluR1a belongs to class of postsynaptic excitatory receptors and has a preferable somatic localization. CRF and NPY were localized using rabbit polyclonal antibodies, and mGluR1a using a mouse monoclonal one. Then, ABC-peroxidase and DAB or benzidine were used. Upon single immunostaining, NPY and CRF were found in some nerve cell bodies and fibres in the amygdala. The immunoreactivity of mGluR1 a was observed in some nerve cells, processes and fibres, especially on the border between the central and the basolateral nuclei and ventrally to that region. Double staining revealed mGluR1 a-IR on some CRF- and NPY-immunoreactive nerve cell bodies and processes. The obtained results indicate that mGlu1a receptors may control at least some NPY and CRF neurons in the amygdala.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Neuropéptido Y/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Inmunohistoquímica , Fibras Nerviosas/metabolismo , Neuronas/metabolismo , RatasRESUMEN
The aim of the present study was to examine a potential beneficial effect of the blockade of metabotropic glutamate receptor subtype 5 (mGluR5) by the selective non-competitive antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), in models of parkinsonian symptoms in rats. Haloperidol, 0.25, 0.5 and 1mg/kg ip, was used to induce hypolocomotion, catalepsy and muscle rigidity, respectively. The locomotor activity was estimated by an open-field test, the catalepsy -- by a 9-cm cork test. The muscle rigidity was measured as an increased resistance of a hind leg to passive extension and flexion at the ankle joint. Additionally, increases in the electromyographic activity were recorded in the gastrocnemius and tibialis anterior muscles. MPEP (1.0-10mg/kg ip) inhibited the muscle rigidity, electromyographic activity, hypolocomotion and catalepsy induced by haloperidol. MPEP administered alone (5mg/kg ip) did not induce catalepsy, nor did it influence the muscle tone or locomotor activity in rats. The present results suggest that blockade of mGluR5 receptors may be important to amelioration of both parkinsonian akinesia and muscle rigidity.
Asunto(s)
Antiparkinsonianos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Antipsicóticos/toxicidad , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Discinesia Inducida por Medicamentos/prevención & control , Electromiografía , Haloperidol/toxicidad , Masculino , Actividad Motora/efectos de los fármacos , Rigidez Muscular/inducido químicamente , Rigidez Muscular/prevención & control , Miografía , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5RESUMEN
Amygdala is the brain structure responsible for integrating all behavior connected with fear, and in this structure two neuropeptides, neuropeptide Y (NPY), corticoliberin (CRF) and the most abundant excitatory neurotransmitter glutamate seem to take part in the regulation of anxiety behavior. Our previous studies showed the modulation of NPY and CRF expression by classical neurotransmitters in some brain structures, therefore in the present study we investigated the effect of NMDA receptor antagonists on the expression of NPY and CRF immunoreactivity in the rat brain amygdala. A non-competitive NMDA receptor antagonist, MK-801, or a functional NMDA antagonist, ACPC were used. Brains were taken out and processed by immunohistochemical method using specific NPY or CRF antibodies. The staining intensity and density of IR neurons were evaluated under a microscope in amygdala sections. It was found that both MK-801 and ACPC induced a significant decrease in NPY-immunoreactivity in amygdala nerve cell bodies and terminals, which may suggest an increased release of this peptide. CRF-IR was decreased after ACPC only. The obtained results indicate that in the amygdala, the NMDA receptors mediated glutamatergic transmission may regulate NPY neurons.
Asunto(s)
Aminoácidos Cíclicos/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Maleato de Dizocilpina/farmacología , Neuronas/efectos de los fármacos , Neuropéptido Y/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Aminoácidos Cíclicos/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/metabolismo , Maleato de Dizocilpina/metabolismo , Masculino , Neuronas/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The aim of our study was to investigate the level of metabotropic glutamate receptors (mGluRs) in the brains of rats after chronic mild stress. Using Western blotting procedure we showed that the level of mGluR5 receptor protein was increased in CA1 and decreased in CA3 region of the hippocampus. Our results indicate that mGluR5 can possibly be engaged in the mechanism of depression.
Asunto(s)
Depresión/metabolismo , Hipocampo/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Western Blotting , Enfermedad Crónica , Giro Dentado/metabolismo , Depresión/etiología , Electroforesis en Gel de Poliacrilamida , Masculino , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Estrés Psicológico/complicacionesRESUMEN
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
The present study was designed to evaluate the effects of bulbectomy and acute administration of anxiolytic drugs (diazepam, 10 mg/kg; chlordiazepoxide, 10 mg/kg) on the behavior of both sham-operated and olfactory bulbectomized rats in two tests predictive of anxiolytic activity: plus-maze test and Vogel's conflict test. We investigated also the effect of flumazenil (10 mg/kg), a benzodiazepine receptors antagonist, both on control and drug-treated animals. We also evaluated behavior of animals in conditioned place aversion procedure. Our results show the decreased level of anxiety in bulbectomized animals comparing with sham-operated rats. Anxiolytic drugs further deepen this effect.
Asunto(s)
Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Bulbo Olfatorio/fisiología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Flumazenil/farmacología , Moduladores del GABA/farmacología , Inyecciones Intraperitoneales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Clinical reports suggest that amisulpride, in addition to its antipsychotic efficacy, may also have antidepressant properties. The present study was designed to evaluate potential antidepressant-like activity of amisulpride in two behavioural procedures: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by subchronic (three injections over a 24 h period) administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. The 5 mg/kg dose of amisulpride was marginally effective and higher doses of 10 and 30 mg/kg were inactive. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). Lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. The magnitude of the effect of active doses of amisulpride in the CMS model was comparable to that of imipramine but its onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed. These results provide further support for clinical observations that amisulpride may possess potent and rapid antidepressant activity.
Asunto(s)
Antidepresivos/farmacología , Antipsicóticos/farmacología , Depresión/psicología , Modelos Animales de Enfermedad , Sulpirida/análogos & derivados , Amisulprida , Animales , Relación Dosis-Respuesta a Droga , Imipramina/farmacología , Masculino , Motivación , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Sulpirida/farmacología , Resultado del TratamientoRESUMEN
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.