RESUMEN
Our recent study has indicated that a moderate lesion induced by bilateral 6-hydroxydopamine (6-OHDA) injections into the ventrolateral region of the caudate-putamen (CP) in rats, modeling preclinical stages of Parkinson's disease, induces a "depressive-like" behavior which is reversed by chronic treatment with pramipexole (PRA). The aim of the present study was to examine the influence of the above lesion and chronic PRA treatment on binding to the serotonin transporter (SERT) in different brain regions. As before, 6-OHDA (15 µg/2.5 µl) was administered bilaterally into the CP. PRA (1mg/kg) was injected subcutaneously twice a day for 2 weeks. Serotonergic and dopaminergic neurons of the dorsal raphe (DR) were immunostained for tryptophan hydroxylase and tyrosine hydroxylase, respectively, and were counted stereologically. Binding of [(3)H]GBR 12,935 to the dopamine transporter (DAT) and [(3)H]citalopram to SERT was analyzed autoradiographically. Intrastriatal 6-OHDA injections decreased the number of dopaminergic, but not serotonergic neurons in the DR. 6-OHDA reduced the DAT binding in the CP, and SERT binding in the nigrostriatal system (CP, substantia nigra (SN)), limbic system (ventral tegmental area (VTA), nucleus accumbens (NAC), amygdala, prefrontal cortex (PFCX), habenula, hippocampus) and DR. A significant positive correlation was found between DAT and SERT binding in the CP. Chronic PRA did not influence DAT binding but reduced SERT binding in the above structures, and deepened the lesion-induced losses in the core region of the NAC, SN, VTA and PFCX. The present study indicates that both the lesion of dopaminergic neurons and chronic PRA administration induce adaptive down-regulation of SERT binding. Moreover, although involvement of stimulation of dopaminergic transmission by chronic PRA in its "antidepressant" effect seems to be prevalent, additional contribution of SERT inhibition cannot be excluded.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Benzotiazoles/administración & dosificación , Encéfalo/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Neostriado/metabolismo , Trastornos Parkinsonianos/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/metabolismo , Núcleo Dorsal del Rafe/diagnóstico por imagen , Núcleo Dorsal del Rafe/efectos de los fármacos , Regulación hacia Abajo , Masculino , Neostriado/diagnóstico por imagen , Neostriado/efectos de los fármacos , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Pramipexol , Cintigrafía , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/metabolismo , Triptófano Hidroxilasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Thiazolidinedione (TZD) class of peroxisome proliferator receptor gamma (PPAR-γ) agonists display neuroprotective effects in experimental Parkinson's disease (PD) models. Neurons and microglia express PPAR-γ, therefore both of them are potential targets for neuroprotection, although the role of each cell type is not clear. Moreover, receptor-dependent as well as receptor-independent mechanisms have been involved. This study further investigated mechanisms of TZD-mediated neuroprotection in PD. We investigated the rosiglitazone effect in the progressive MPTP/probenecid (MPTPp) model of PD. C57BL/6J mice received MPTP (25 mg/kg) plus probenecid (100 mg/kg) twice per week for 5 weeks. Rosiglitazone (10 mg/kg) was given daily until sacrifice, starting on the fourth week of MPTPp treatment, in presence of an ongoing neurodegeneration with microgliosis. Changes in PPAR-γ levels were measured by immunofluorescence and confocal microscopy in tyrosine hydroxylase (TH)-positive neurons and CD11b-positive microglia of the substantia nigra pars compacta (SNc). Chronic MPTPp treatment induced a PPAR-γ overexpression in both TH-positive neurons and microglia (139.9% and 121.7% over vehicle, respectively). Rosiglitazone administration to MPTPp-treated mice, reverted PPAR-γ overexpression in microglia without affecting TH-positive neurons. Thereafter, changes in CD11b and tumor necrosis factor α (TNF-α) immunoreactivity in microglia were evaluated in the SNc. MPTPp progressively increased CD11b immunoreactivity, conferring to microglia a highly activated morphology. Moreover, TNF-α levels were increased (457.38% over vehicle) after MPTPp. Rosiglitazone administration counteracted the increase in CD11b immunoreactivity caused by MPTPp. Moreover, rosiglitazone reverted TNF-α expression to control levels. Nigrostriatal degeneration was assessed by high pressure liquid chromatography (HPLC) measurement of striatal dopamine, and counting of TH-positive neurons in the SNc. MPTPp treatment caused a severe decline of striatal dopamine and a partial degeneration of the SNc. Rosiglitazone arrested the degenerative process in both areas. Results suggest that PPAR-γ expression in microglia and TNF-α production by these cells are crucial changes by which rosiglitazone exerts neuroprotection in PD.
Asunto(s)
Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , PPAR gamma/antagonistas & inhibidores , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/metabolismo , Tiazolidinedionas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/patología , PPAR gamma/metabolismo , Trastornos Parkinsonianos/patología , Rosiglitazona , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Group III metabotropic glutamate receptors (mGluRs) are widely distributed in the basal ganglia, especially on the terminals of pathways which seem to be overactive in Parkinson's disease. The aim of the present study was to determine whether (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-1), an agonist of group III mGluRs, injected bilaterally into the globus pallidus (GP), striatum or substantia nigra pars reticulata (SNr), can attenuate the haloperidol-induced catalepsy in rats, and whether that effect was related to modulation of proenkephalin (PENK) or prodynorphin (PDYN) mRNA expression in the striatum. Administration of ACPT-1 (0.05-1.6 microg/0.5 microl/side) caused a dose-and-structure-dependent decrease in the haloperidol (0.5 mg/kg i.p. or 1.5 mg/kg s.c.)-induced catalepsy whose order was as follows: GP>striatum>SNr. ACPT-1, given alone to any of those structures, induced no catalepsy in rats. Haloperidol (3 x 1.5 mg/kg s.c.) significantly increased PENK mRNA expression in the striatum, while PDYN mRNA levels were not affected by that treatment. ACPT-1 (3 x 1.6 microg/0.5 microl/side) injected into the striatum significantly attenuated the haloperidol-increased PENK mRNA expression, whereas administration of that compound into the GP or SNr did not influence the haloperidol-increased striatal PENK mRNA levels. Our results demonstrate that stimulation of group III mGluRs in the striatum, GP or SNr exerts antiparkinsonian-like effects in rats. The anticataleptic effect of intrastriatally injected ACPT-1 seems to correlate with diminished striatal PENK mRNA expression. However, since the anticataleptic effect produced by intrapallidal and intranigral injection of ACPT-1 is not related to a simultaneous decrease in striatal PENK mRNA levels, it is likely that a decrease in enkephalin biosynthesis is not a necessary condition to obtain an antiparkinsonian effect.
Asunto(s)
Cuerpo Estriado/metabolismo , Ciclopentanos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Vías Nerviosas/metabolismo , Péptidos Opioides/genética , Trastornos Parkinsonianos/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Ácidos Tricarboxílicos/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Antagonistas de Dopamina/efectos adversos , Relación Dosis-Respuesta a Droga , Encefalinas/biosíntesis , Encefalinas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Ácido Glutámico/metabolismo , Haloperidol/efectos adversos , Haloperidol/antagonistas & inhibidores , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Péptidos Opioides/biosíntesis , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Precursores de Proteínas/biosíntesis , Precursores de Proteínas/genética , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
Several data indicate that inhibition of glutamatergic transmission may be important to alleviate of parkinsonian symptoms. Therefore, the aim of the present paper is to review recent studies on the search for putative antiparkinsonian-like effects of mGluR ligands and their brain targets. In order to inhibit glutamatergic transmission, the group I mGluRs (mGluR1 and mGluR5) were blocked, and group II (mGluR2/3) or III (mGluR4/7/8) mGluRs were activated. Systemic or intrastriatal administration of group I mGluR antagonists (mGluR5 - MPEP, MTEP; mGluR1 - AIDA) was found to inhibit parkinsonian-like symptoms (catalepsy, muscle rigidity) in rats. MPEP administered systemically and mGluR1 antagonists (AIDA, CPCCOEt, LY367385) injected intrastriatally reversed also the haloperidol-increased proenkephalin (PENK) mRNA expression in the striatopallidal pathway. Similarly, ACPT-1, a group III mGluR agonist, administered into the striatum, globus pallidus or substantia nigra inhibited the catalepsy. Intrastriatal injection of this compound reduced the striatal PENK expression induced by haloperidol. In contrast, a group II mGluR agonist (2R,4R-APDC) administered intrastriatally reduced neither PENK expression nor the above-mentioned parkinsonian-like symptoms. Moreover, a mixed mGluR8 agonist/AMPA antagonist, (R,S)-3,4-DCPG, administered systemically evoked catalepsy and enhanced both the catalepsy and PENK expression induced by haloperidol. The results reviewed in this article seem to indicate that group I mGluR antagonists or some agonists of group III may possess antiparkinsonian properties, and point at the striatopallidal pathway as a potential target of therapeutic intervention.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Benzoatos/farmacología , Catalepsia , Cuerpo Estriado/metabolismo , Encefalinas/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Glutamatos/metabolismo , Glicina/análogos & derivados , Glicina/farmacología , Haloperidol/farmacología , Humanos , Ligandos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Ratas , Receptores de Glutamato Metabotrópico/químicaRESUMEN
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 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
Overactivity of the striatopallidal pathway, associated with an enhancement of enkephalin expression, has been suggested to contribute to the development of parkinsonian symptoms. The aim of the present study was to examine whether the blockade of group I metabotropic glutamate receptors: subtypes 1 and 5 (mGluR1/5), or stimulation of group II: subtypes 2 and 3 (mGluR2/3) may normalize enkephalin expression in the striatopallidal pathway in an animal model of parkinsonism. The proenkephalin mRNA level measured by in situ hybridization in the striatum was increased by pretreatments with haloperidol (1.5 mg/kg s.c., three times, 3 h apart). Triple (3 h apart), bilateral, intrastriatal administration of selective antagonists of mGluR1: (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (3 x 5 microg/0.5 microl) or 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate (3 x 2.5 microg/0.5 microl), reversed the haloperidol-induced increases in proenkephalin mRNA levels in the rostral and central regions of the striatum. Similarly, repeated (6 times, 1.5 h apart), systemic injections of an antagonist of mGluR5, 2-methyl-6-(phenylethynyl)pyridine (6 x 10 mg/kg i.p.) counteracted an increase in the striatal proenkephalin mRNA expression elicited by haloperidol. None of the abovementioned antagonists of mGluR1 and mGluR5 per se influenced the proenkephalin expression. Differential effects were induced by agonists of the group II mGluRs, viz. (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine administered intraventricularly (3 times at 0.1-0.2 microg/4 microl, 3 h apart) increased both the normal and haloperidol-increased proenkephalin mRNA level, whereas (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate injected intrastriatally (3 times at 15 microg/0.5 microl, 3 h apart) was ineffective. The present study indicates that the blockade of striatal glutamate receptors belonging to the group I (mGluR1 and mGluR5) but not stimulation of the group II mGluRs may normalize the function of the striatopallidal pathway in an animal model of parkinsonism, which may be important for future antiparkinsonian therapy in humans.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Encefalinas/metabolismo , Enfermedad de Parkinson/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacología , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Encefalinas/genética , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Haloperidol/farmacología , Hibridación in Situ , Masculino , Enfermedad de Parkinson/genética , Precursores de Proteínas/genética , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
The aim of the present study was to find out whether (+/-)-8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical 5-HT1A agonist, and (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with serotonin 5-HT1A-agonist and dopamine D2-like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously measured the mechanical muscle resistance (MMG) of the rat's hind foot to passive movements in the ankle joint, and the EMG activity of two antagonist muscles. Both 8-OH-DPAT (0.125-0.5 mg/kg i.p.) and EMD 128130 (1-10 mg/kg i.p.) dose-dependently decreased the haloperidol-enhanced MMG to passive movements, as well as the tonic and the long-latency reflex EMG activities. Provided these results can be extrapolated to humans, the efficacy of EMD 128130 in relieving the haloperidol-induced muscle rigidity supports the concept that novel antipsychotics with 5-HT1A agonist and dopamine D2 antagonist activities should have a favourable extrapyramidal side-effect profile.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Antiparkinsonianos/farmacología , Haloperidol/toxicidad , Rigidez Muscular/inducido químicamente , Agonistas del Receptor de Serotonina 5-HT1 , Animales , Masculino , Rigidez Muscular/fisiopatología , Compuestos Orgánicos , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/fisiología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
The primary cause of Parkinson's disease is a loss of dopamine in the corpus striatum. It has been postulated that this effect leads to disinhibition of the striopallidal pathway and secondarily, to a functional shift towards glutamatergic stimulation. The aim of the present study was to find out whether inhibition of glutamatergic transmission at a level of metabotropic glutamate receptors (mGluRs) in the striatum may alleviate parkinsonian-like symptoms in rats. The non-competitive antagonist of receptor subtype 5 (mGluR5), MPEP (1.0-10 mg/kg ip), or the agonist of group II mGluRs, LY354,740 (5-10 mg/kg ip), reduced haloperidol-induced muscle rigidity and catalepsy. Intrastriatal injections of the mGluR1 antagonist, (RS) AIDA (7.5-15 microg/0.5 microl), but not of the agonist of group II mGluRs, 2R,4R-APDC (7.5-15 microg/0.5 microl), inhibited the muscle rigidity induced by haloperidol. In order to search for an influence of mGluRs on the striopallidal pathway, the effect of MPEP or of the agonist of group II mGluRs, DCG-IV, on the proenkephalin (PENK) mRNA expression in the dorso-lateral striatum was examined by an in situ hybridization. Repeated MPEP (6 x 10 mg/kg ip) administration did not influence PENK expression in naïve rats, but diminished that increased by haloperidol. In contrast, repeated DCG-IV (3 x 1 nmol/4 microl icv) injections enhanced both the control and the haloperidol-increased levels of PENK expression. The obtained results suggest that blockade of group I mGluRs, or stimulation of group II mGluRs may be important to ameliorate parkinsonian symptoms. Striatal mGluRs may contribute to at least some of these effects.
Asunto(s)
Cuerpo Estriado/metabolismo , Enfermedad de Parkinson/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Antiparkinsonianos/metabolismo , Antiparkinsonianos/uso terapéutico , Cuerpo Estriado/citología , Encefalinas/metabolismo , Agonistas de Aminoácidos Excitadores/metabolismo , Agonistas de Aminoácidos Excitadores/uso terapéutico , Antagonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Ligandos , Enfermedad de Parkinson/tratamiento farmacológico , Isoformas de Proteínas/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Glutamato Metabotrópico/químicaRESUMEN
The aim of the present study was to find out whether blockade of adenosine A(2A) receptors by a selective antagonist, SCH 58261, influenced parkinsonian-like muscle rigidity. Muscle tone was examined using a combined mechano- and electromyographic method which simultaneously measured muscle resistance (MMG) of a rat hindfoot to passive extension and flexion in the ankle joint and electromyographic activity (EMG) of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity produced by reserpine (5 mg/kg + alpha-methyl-p-tyrosine, 250 mg/kg) was antagonized by SCH 58261 (0.1-5 mg/kg). SCH 58261 (5 mg/kg) also reduced reserpine-enhanced tonic and reflex EMG activities in both the gastrocnemius and the tibialis muscles. Moreover, SCH 58261 in doses of 1 and 5 mg/kg abolished muscle resistance induced by haloperidol (0.5 mg/kg). However, only the highest dose of SCH 58261 (5 mg/kg) decreased tonic EMG activity enhanced by haloperidol. Administration of L-DOPA (75 and 100 mg/kg) dose-dependently decreased the muscle resistance as well as tonic EMG activity evoked by haloperidol. Combined administration of SCH 58261 (0.1 mg/kg) and L-DOPA (50 mg/kg) in doses which did not affect the haloperidol-induced muscle rigidity produced a pronounced synergistic effect. The ability of SCH 58261 to diminish the parkinsonian-like muscle rigidity and to potentiate the effect of L-DOPA in this model seems to indicate a therapeutic value of this compound in the treatment of Parkinson's disease.
Asunto(s)
Rigidez Muscular/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/farmacología , Receptores Purinérgicos P1/metabolismo , Triazoles/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Animales , Articulación del Tobillo/efectos de los fármacos , Articulación del Tobillo/fisiología , Dopaminérgicos/farmacología , Antagonistas de Dopamina/farmacología , Combinación de Medicamentos , Electromiografía , Haloperidol/farmacología , Levodopa/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neostriado/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , Receptor de Adenosina A2A , Reserpina/farmacologíaRESUMEN
The aim of the study was to assess the contribution of central dopaminergic and glutamatergic systems to the age-dependent loss of motor functions in rats. Rats of three age groups were compared: young (3-5-month-old), middle-aged (20-21-month-old) and old (29-31-month-old). The obtained results showed an age-dependent decline in the electromyographic (EMG) resting and reflex activities in the gastrocnemius and tibialis anterior muscles, as well as in the T-maze performance. Although these disturbances were accompanied with significant age-dependent decreases in the binding to NMDA, AMPA and dopamine D2 receptors, and a decline in the number of nigral dopamine neurons, they were significantly correlated with the loss of the binding to NMDA receptors only. The reduction in T-maze performance with aging was additionally correlated with a decrease in motor functions (EMG activity). The study suggests a crucial role of the loss of NMDA receptors in age-dependent motor disabilities, as well as in disturbances measured in the T-maze.
Asunto(s)
Envejecimiento/metabolismo , Dopamina/fisiología , Ácido Glutámico/fisiología , Trastornos del Movimiento/etiología , Proteínas del Tejido Nervioso/análisis , Receptores de N-Metil-D-Aspartato/análisis , Envejecimiento/psicología , Animales , Articulación del Tobillo/fisiopatología , Biomarcadores , Fenómenos Biomecánicos , Mapeo Encefálico , Recuento de Células , Maleato de Dizocilpina/metabolismo , Electromiografía , Femenino , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/metabolismo , Discapacidades para el Aprendizaje/patología , Aprendizaje por Laberinto , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Proteínas del Tejido Nervioso/fisiología , Docilidad , Desempeño Psicomotor , Racloprida/metabolismo , Ratas , Ratas Wistar , Tiempo de Reacción , Receptores AMPA/análisis , Receptores AMPA/metabolismo , Receptores de Dopamina D2/análisis , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/análisis , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
The aim of the present study was to determine whether S-4-carboxy-3-hydroxyphenylglycine (S)-4C3HPG, a mixed group I glutamate metabotropic receptor antagonist and a group II agonist, attenuated parkinsonian-like muscle rigidity in rats. Muscle tone was examined using a combined mechano and electromyographic method, which measured simultaneously the muscle resistance (MMG) of the rat's hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles of that joint: gastrocnemius and tibialis anterior. Muscle rigidity was induced by pretreatment with haloperidol (1 mg/kg i.p.). (S)-4C3HPG injected in doses of 5 and 15 microg/0.5 microl bilaterally, into the rostral region of the striatum, decreased both the haloperidol-induced muscle rigidity (MMG) and the enhanced electromyographic activity (EMG). The present results suggest that blockade of mGluR1 receptors and/or activation of mGluR2 ones, localized in the rostral part of the striatum, may be responsible for the anti-parkinsonian effect of (S)-4C3HPG.
Asunto(s)
Cuerpo Estriado/fisiopatología , Glicina/farmacología , Rigidez Muscular/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Antidiscinéticos , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Electromiografía , Glicina/análogos & derivados , Haloperidol , Masculino , Microinyecciones , Rigidez Muscular/inducido químicamente , Rigidez Muscular/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , Tarso Animal/fisiologíaRESUMEN
The most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A(2A) receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A(2A) antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Fos-like-immunoreactivity in neurons of the lesioned striatum. Likewise, other A(2A) receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-diethyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dihydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A(2A) receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A(2A) antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the MPTP model of PD. Adenosine A(2A) receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.
RESUMEN
It has recently been postulated that disturbances in glutamatergic neurotransmission may contribute to the pathophysiology of schizophrenia. Therefore the aim of the present study was to evaluate the role of glutamate NMDA and group II metabotropic receptors in the antipsychotic drug action. To this aim the influence of some well-known neuroleptics on cortical NMDA receptors was examined. Furthermore, their behavioral effects were compared with those of the novel agonist of group II glutamate metabotropic receptors, LY 354740, in some animal models of schizophrenic deficits. We found that long-term administration of the typical neuroleptic haloperidol and the atypical one clozapine increased the number of NMDA receptors labelled with [3H]CGP 39653 in different cortical areas. Long-, but not short-term, treatment with haloperidol and raclopride diminished the deficit of prepulse inhibition produced by phencyclidine, which is a model of sensorimotor gating deficit in schizophrenia. In contrast, neither short- nor long-term treatment with clozapine influenced the phencyclidine effect in that model. Acute treatment with LY 354740 reversed neither (1) the deficit of prepulse inhibition produced by phencyclidine or apomorphine, nor (2) the impairment in a delayed alternation task induced by MK-801, which is commonly used to model the frontal lobe deficits associated with schizophrenia. The present study suggests that an increase in the density of cortical NMDA receptors may be important to a longterm neuroleptic therapy. Conversely, the results do not support the role of group II metabotropic glutamate receptors in the antipsychotic drug action.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Antipsicóticos/farmacología , Receptores de Glutamato Metabotrópico/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Compuestos Bicíclicos con Puentes/farmacología , Fenciclidina/farmacología , RatasRESUMEN
The aim of this study was to examine the role of cortical NMDA receptors in the antipsychotic action of neuroleptics. Haloperidol (1 mg/kg/day) and clozapine (30 mg/kg/day) were administered to rats in drinking water. Autoradiographic and saturation binding analyses showed that a 3-month treatment with both haloperidol and clozapine increased the density of NMDA receptors labelled with [3H]CGP 39653 (a competitive antagonist) in the parietal and insular cortices. Haloperidol additionally increased the binding of that ligand in the frontal cortex. None of those neuroleptics influenced the binding of [3H]MK-801, an uncompetitive antagonist of NMDA receptors, in the frontal, parietal or insular cortices. A 6-week and a 3-month treatment with haloperidol antagonized the deficit of prepulse inhibition induced by phencyclidine (5 mg/kg s.c.). In contrast, short-term (4-day) administration of that neuroleptic was ineffective. The present study suggests that the increased density of cortical NMDA receptors, induced by long-term neuroleptic administration, may overcome the deficit of sensorimotor gating induced by phencyclidine. However, contribution of such an effect to the antipsychotic activity needs to be established.
Asunto(s)
Conducta Animal/efectos de los fármacos , Corteza Cerebral/fisiología , Clozapina/farmacología , Haloperidol/farmacología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Antipsicóticos/farmacología , Fenciclidina/farmacología , Ratas , Factores de TiempoRESUMEN
The aim of the present study was to examine the influence of 3-month administration of haloperidol (1 mg/kg per day) and clozapine (30 mg/kg per day) in drinking water on cortical NMDA (N-methyl-D-aspartate) receptors in rats. On day 5 of withdrawal, the animals were killed and their brains were removed. The binding of [3H]MK-801 ([3H](5R, 10S)-(+)-5-methyl-10,1 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) and [3H]CGP 39653([3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) to NMDA receptors in different cortical areas, as well as the binding of [3H]spiperone to dopamine D2 receptors in the striatum, were analysed by quantitative autoradiography. Haloperidol increased the binding of [3H]CGP 39653 in frontal, insular and parietal cortices. Clozapine increased the binding of [3H]CGP 39653 in insular and parietal cortices. Haloperidol, but not clozapine, increased the binding of [3H]spiperone in the striatum. None of the neuroleptics influenced the binding of [3H]MK-801 to cortical NMDA receptors. An additional assay revealed an increase in the Bmax value, with no significant changes in the K(D) of [3H]CGP 39653 binding in parieto-insular cortical homo-genates as a result of haloperidol and clozapine administration. The present results suggest that long-term treatments with haloperidol and clozapine increase the number of NMDA receptors in different cortical regions.
Asunto(s)
Antipsicóticos/farmacología , Corteza Cerebral/efectos de los fármacos , Clozapina/farmacología , Haloperidol/farmacología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/metabolismo , Animales , Autorradiografía , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Maleato de Dizocilpina/metabolismo , Masculino , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Espiperona/metabolismo , TritioRESUMEN
Acute administration of the atypical antipsychotic clozapine induced a regional pattern of c-fos expression characterized by an increase in Fos-like-immunoreactivity (FLI) in the prefrontal and prelimbic/infralimbic cortices, nucleus accumbens, and lateral septum and a weak activation of FLI in the striatum. Haloperidol, similarly to clozapine, increased FLI in the nucleus accumbens and lateral septum, but it did not induce FLI in prefrontal and prelimbic/infralimbic cortices. Moreover, haloperidol increased FLI in the striatum. To gain insight into the mechanism by which clozapine and haloperidol induced FLI in these brain structures, we evaluated whether blockade of adenosine A2A receptors could influence these effects. The selective and high-affinity A2A receptor antagonist SCH 58261 (5 mg/kg) completely abolished FLI induced by clozapine (20 mg/kg) in all subdivisions of the nucleus accumbens (rostral pole, shell and core) and striatum, but did not affect the number of Fos-like positive neurons in the prefrontal, prelimbic/infralimbic cortices, and lateral septum. SCH 58261 (5 mg/kg) reduced FLI induced by haloperidol (0.1 mg/kg) in the striatum, lateral septum, and all nucleus accumbens subdivisions. In contrast, FLI induced by 0.5 mg/kg of haloperidol in the shell and core of the nucleus accumbens was not affected by SCH 58261. The results show that adenosine A2A receptors participate in the induction of FLI by clozapine and haloperidol and support the concept that A2A receptors are involved in the mediation of antipsychotic effects.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Genes fos/efectos de los fármacos , Haloperidol/farmacología , Neuronas/efectos de los fármacos , Receptores Purinérgicos P1/metabolismo , Animales , Expresión Génica/efectos de los fármacos , Masculino , Neuronas/metabolismo , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A , Triazoles/farmacologíaRESUMEN
The aim of the present study was to assess contribution of striatal adenosine A2A receptors to regulation of the muscle tone in rats. The muscle tone was examined by a combined mechano- and electromyographic method, which measured simultaneously muscle resistance (MMG) of a rats hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles: gastrocnemius and tibialis anterior. CGS 21680 (1 and 2 microg/0.5 microl), injected bilaterally into the rostral part of the striatum, dose-dependently increased both MMG and the EMG. The present results show that stimulation of striatal adenosine A2A receptors by CGS 21680 evokes parkinsonian-like muscle rigidity which may be due to activation of the GABAergic strio-pallidal pathway.
Asunto(s)
Adenosina/análogos & derivados , Articulación del Tobillo/efectos de los fármacos , Rigidez Muscular/fisiopatología , Tono Muscular/efectos de los fármacos , Fenetilaminas/farmacología , Agonistas del Receptor Purinérgico P1 , Receptores Purinérgicos P1/efectos de los fármacos , Adenosina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Electromiografía , Masculino , Tono Muscular/fisiología , Ratas , Ratas Wistar , Receptor de Adenosina A2A , Receptores Purinérgicos P1/fisiologíaRESUMEN
Expression of the early-gene c-fos is an useful method for studying potential sites of action of drugs active in the CNS. Stimulation of adenosine A2A receptors by CGS 21680 (5 mg/kg) induced an increase in Fos-like immunoreactivity in the rat nucleus accumbens shell, while in the rostral pole and core CGS 21680 induced Fos-like immunoreactivity only after a high dose. CGS 21680 (5 mg/kg) stimulated c-fos expression also in the lateral septal nucleus and dorso-medial striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A2A agonist HENECA (5 mg/kg) which displays higher selectivity for A2A receptors than CGS 21680. Administration of the selective A2A antagonist SCH 58261 counteracted CGS 21680-induced Fos-like immunoreactivity. Lesions of the dopaminergic mesostriatal projection by 6-hydroxydopamine and stimulation of dopamine D2/D3 receptors by quinpirole, prevented CGS 21680-induced Fos-like immunoreactivity in the nucleus accumbens shell. The present results show that stimulation of A2A receptors induces a profile of c-fos expression similar to that of atypical neuroleptics. A2A receptor stimulation has been reported to have dopamine antagonistic actions, it is therefore suggested that A2A agonists might have antipsychotic activity without producing extrapyramidal side effects.
Asunto(s)
Adenosina-5'-(N-etilcarboxamida)/análogos & derivados , Sistema Límbico/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Agonistas del Receptor Purinérgico P1 , Adenosina/análogos & derivados , Adenosina/antagonistas & inhibidores , Adenosina/farmacología , Animales , Agonistas de Dopamina/farmacología , Inmunohistoquímica , Sistema Límbico/efectos de los fármacos , Masculino , Oxidopamina/farmacología , Fenetilaminas/antagonistas & inhibidores , Fenetilaminas/farmacología , Antagonistas Purinérgicos , Pirimidinas/farmacología , Quinpirol/farmacología , Ratas , Ratas Sprague-Dawley , Triazoles/farmacologíaRESUMEN
The aim of the present study was to evaluate age-related changes in NMDA and AMPA receptors in old female rats. To this end a quantitative autoradiography of [3H]-MK-801 and [3H]-AMPA binding was performed in the brain of young (3-month-old), middle-aged (12-month-old) and old (36-month-old) rats. Moreover, the binding of [3H]-spiperone to D2 dopamine receptors was also examined. No changes were observed in the binding of [3H]-MK-801 or [3H]-AMPA in middle-aged rats compared to young ones. In the caudate-putamen and shell and core of the nucleus accumbens septi of old rats, a pronounced decrease in the [3H]-MK-801 binding and a decreasing tendency in the [3H]-AMPA binding were observed. Furthermore, the binding of [3H]-MK-801 and [3H]-AMPA was reduced in the hippocampal formation and, additionally, a marked decline in the [3H]-MK-801 binding in different parts of the cerebral cortex including the frontal, parietal, cingulate, pyriform and insular cortices was found. The [3H]-spiperone binding progressively decreased with age in the dorsolateral, ventrolateral and medial caudate-putamen. The present results show that aging processes lead to changes in the binding of both [3H]-MK-801 to NMDA and [3H]-AMPA to AMPA receptors in a number of structures, a phenomenon which may reflect motor and memory disturbances found in old rats and elderly humans.