RESUMEN
The globus pallidus sends a significant GABAergic projection to the thalamic reticular nucleus. Because pallidal neurons express D4-dopamine receptors, we have explored their presence on pallidoreticular terminals by studying the effect of dopamine and D4-receptor agonists on the GABAergic transmission in the thalamic reticular nucleus. We made whole-cell recordings of inhibitory postsynaptic currents (IPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in the thalamic reticular neurons. Dopamine consistently reduced the IPSCs. The effect of dopamine was associated with paired-pulse facilitation, indicating a presynaptic location of the receptors. The effect of dopamine was also measured on the mIPSCs, reducing their frequency but not affecting their amplitude, which also suggests a presynaptic site of action. The selective D4-receptor agonist PD 168,077 also reduced the IPSCs, which was also associated with paired-pulse facilitation. In addition, this agonist reduced the frequency of the mIPSCs with no effect on their amplitude. The D4-receptor antagonist L-745,870 totally blocked the effect of the D4-receptor agonist, indicating the specificity of its effect. To verify the location of the receptors on the pallidal terminals, these were eliminated by injecting kainic acid into the globus pallidus. Kainic acid produced a drastic (80%) fall in the globus pallidus neuronal population. In this condition, the effect of the activation of D4 receptors both on the IPSCs and mIPSCs was prevented, thus indicating that the location of the receptors was on the pallidal terminals. Our results demonstrate that dopamine controls the activity of the thalamic reticular neurons by regulating the inhibitory input from the globus pallidus.
Asunto(s)
Dopamina/fisiología , Globo Pálido/metabolismo , Núcleos Talámicos Intralaminares/metabolismo , Terminales Presinápticos/metabolismo , Receptores de Dopamina D4/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Dopamina/farmacología , Globo Pálido/citología , Globo Pálido/efectos de los fármacos , Núcleos Talámicos Intralaminares/efectos de los fármacos , Masculino , Vías Nerviosas/citología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Técnicas de Cultivo de Órganos , Terminales Presinápticos/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Dopamina D4/agonistasRESUMEN
The present study investigates the effects of divalent and trivalent manganese (Mn(2+)/Mn(3+)) mixture inhalation on mice to obtain a novel animal model of Parkinson disease (PD) inducing bilateral and progressive cell death in the substantia nigra compacta (SNc) and correlating these alterations with motor disturbances. CD-1 male mice inhaled a mixture of 0.04 M manganese chloride (MnCl(2)) and manganese acetate (Mn(OAc)(3)), 1 h twice a week for 5 months. Before Mn exposure, animals were trained to perform motor function tests and were evaluated each week after the exposure. By doing this, overall behavior was assessed by ratings and by videotaped analyses; by the end of Mn exposure period, animals were killed. The mesencephalon was processed for tyrosine hydroxylase (TH) immunocytochemistry. After 5 months of Mn mixture inhalation, mice developed evident deficits in their motor performance manifested as akinesia, postural instability and action tremor. SNc of the Mn-exposed animals showed an important decrease (67.58%) in the number of TH-immunopositive neurons. Our data provide evidence that MnCl(2) and Mn(OAc)(3) mixture inhalation produces similar morphological and behavioral alterations to those observed in PD providing a useful experimental model for the study of this neurodegenerative disease.
Asunto(s)
Acetatos/toxicidad , Conducta Animal/efectos de los fármacos , Cloruros/toxicidad , Modelos Animales de Enfermedad , Exposición por Inhalación , Compuestos Organometálicos/toxicidad , Enfermedad de Parkinson , Animales , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Masculino , Compuestos de Manganeso , Ratones , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Desempeño Psicomotor/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The projections of the substantia nigra pars compacta (SNc) to the reticular thalamic nucleus (RTn) were assessed by measuring dopamine content and counting tyrosine hydroxylase positive (TH (+)) cells in rats with unilateral lesions induced by 6-hydroxydopamine (6-OHDA), and by using a fluorescent tract-tracing technique in rats without lesions. Injection of 6-OHDA in the RTn reduced dopamine content and the number of TH (+) cells in the SNc by about 50%. Branching of SNc was suggested by the finding that 6-OHDA deposited in the RTn significantly reduced dopamine in the striatum and globus pallidus. Moreover, injections of 6-OHDA into either the striatum or the globus pallidus significantly reduced dopamine content in the RTn. Fluorescent tracers injected into the RTn labeled TH (+) cells in the SNc. A high proportion of these TH (+) cells was double labeled when tracers were also injected into either the globus pallidus or striatum. Other experiments showed that systemic injection of apomorphine or methamphetamine induced turning behavior in rats with local deposits of 6-OHDA in either the RTn or the studied basal ganglia nuclei. The extensive dopaminergic branching suggests that the abnormal motor behavior of rats with 6-OHDA deposits in the RTn may be caused by dopaminergic denervation of more than one structure. The fact that lesion of a single dopaminergic neuron can reduce dopamine transmission in more than one structure is probably important in generating the manifestations of Parkinson's disease.
Asunto(s)
Cuerpo Estriado/anatomía & histología , Globo Pálido/anatomía & histología , Actividad Motora/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Sustancia Negra/citología , Adrenérgicos/farmacología , Anfetamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Dextranos/metabolismo , Dopamina/metabolismo , Dopaminérgicos/farmacología , Lateralidad Funcional , Inmunohistoquímica/métodos , Masculino , Actividad Motora/efectos de los fármacos , Oxidopamina/farmacología , Ratas , Ratas Wistar , Núcleos Talámicos/anatomía & histología , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND: Because of their lack of long-term viability, adrenal tissue transplants have shown limited success in alleviating the motor disturbances associated with experimental and pathologic striatal dopamine denervation. In this study, we examined how the graft placement site influences adrenal medulla transplant survival and its relation with the reduction of motor deficits in rats bearing unilateral 6-OHDA lesion. METHODS: One or 5 microL of fetal adrenal medullar tissue was grafted either inside the striatal parenchyma or into the lateral ventricle in contact with the dopamine-denervated striatum. Motor disturbances, as assessed by apomorphine-induced rotation, were correlated to the graft morphologic survival features. RESULTS: Apomorphine-induced rotation showed a marginal reduction of 11% in all groups independently of graft survival features or placement site. Intrastriatal transplants showed limited viability characterized by a substantial loss of graft initial volume as well as fewer and smaller chromaffin cells compared to ventricular grafts, which had a reduced loss of graft initial volume and more and larger chromaffin cells. CONCLUSIONS: Although the lateral ventricle may favor adrenal medulla transplant viability, their induced motor outcome is comparable to that induced by less viable intrastriatal grafts, suggesting that the implanted dopamine-producing cells may interact and influence striatal neurons better when placed in close proximity.