RESUMO
Although the long-term neurobiological and behavioral effects of nigrostriatal lesions are well characterized, the events occurring soon after injury are not. These acute events can provide insight into the mechanisms underlying long-term adaptations to nigrostriatal lesions. The present experiments examined the basal ganglia immediate-early gene response to infusions of the catecholamine neurotoxin 6-hydroxydopamine into the nigrostriatal pathway in rats. Following 6-hydroxydopamine infusions into the medial forebrain bundle in awake, behaving rats, there was a rapid and transient induction of striatal c-fos and zif/268 messenger RNAs. Both immediate-early genes were maximally induced by 45min post-infusion, and returned to control levels by 1.5h (c-fos) or 3h (zif/268) post-infusion. Double-labeling experiments revealed that striatal c-fos expression occurred preferentially in preproenkephalin-expressing neurons. 6-Hydroxydopamine-induced c-fos messenger RNA was also observed in the substantia nigra pars reticulata and entopeduncular nucleus, but not the globus pallidus, 45 min after medial forebrain bundle 6-hydroxydopamine infusions. Finally, the role of ionotropic striatal glutamate receptors in nigrostriatal injury-induced striatal c-fos was examined by combining medial forebrain bundle 6-hydroxydopamine infusions with intrastriatal glutamate antagonist infusions. Both the N-methyl-D-aspartate antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, and the non-N-methyl-D-aspartate antagonist, 6,7-dinitroquinoxaline-2, 3-dione, blocked striatal induction of c-fos messenger RNA following 6-hydroxydopamine infusions into the medial forebrain bundle. These results provide evidence of rapidly developing, glutamate-dependent molecular responses in the basal ganglia which may contribute to some of the well-described long-term adaptations of this system to nigrostriatal injury.
Assuntos
Expressão Gênica , Genes Precoces/genética , Feixe Prosencefálico Mediano/efeitos dos fármacos , Feixe Prosencefálico Mediano/fisiopatologia , Oxidopamina/farmacologia , Animais , Gânglios da Base/metabolismo , Comportamento Animal , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Feixe Prosencefálico Mediano/patologia , Atividade Motora , Piperazinas/farmacologia , Quinoxalinas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sensação , Fatores de TempoRESUMO
The present study examines dopaminergic regulation of neuropeptide gene expression within a relatively poorly characterized population of cells, the preproenkephalin (PPE) mRNA containing neurons of the globus pallidus (GP). Rats that received 6-hydroxydopamine (6-OHDA) lesions or repeated D1 or D2 antagonist administration were compared to control animals. One month after 6-OHDA lesions, PPE mRNA was elevated in the GP ipsilateral to the lesion, with a smaller elevation also being observed in the contralateral GP. Repeated administration of eticlopride, but not SCH 23390, also resulted in elevated PPE mRNA expression in the GP. These data reveal a novel effect of decreased dopamine transmission on the GP, and draw attention to this subpopulation of pallidal neurons.
Assuntos
Dopamina/fisiologia , Encefalinas/genética , Globo Pálido/química , Globo Pálido/fisiologia , Precursores de Proteínas/genética , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Globo Pálido/citologia , Masculino , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Oxidopamina , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Salicilamidas/farmacologia , Substância Negra/química , Substância Negra/citologia , Substância Negra/fisiologia , Radioisótopos de Enxofre , SimpatolíticosRESUMO
To assess the role of striatal glutamatergic synapses in mediating sensorimotor orientation behavior, glutamate receptor antagonists were infused into the left striatum of awake rats and behavioral orientation to contralateral and ipsilateral stimuli were quantified. The AMPA-kainate antagonist, DNQX, and the NMDA antagonist, CPP, both induced a large asymmetry in responding, such that the rats oriented much less to stimuli presented contralateral to the antagonist infusions. Furthermore, intrastriatal glutamate antagonist infusions increased the occurrence of incorrect responses, or turning away from a contralaterally-presented stimulus. In a separate experiment, intrastriatal DNQX was shown to block kainic acid (KA)-induced Fos expression in the striatum, but not in adjacent cerebral cortex, suggesting that the diffusion of this drug is restricted to the striatum.
Assuntos
Atenção/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Lateralidade Funcional , Orientação/efeitos dos fármacos , Piperazinas/farmacologia , Quinoxalinas/farmacologia , Estimulação Acústica , Animais , Masculino , Estimulação Luminosa , Ratos , Tato/fisiologiaRESUMO
The 6-hydroxydopamine rat model of Parkinson's disease was combined with intracerebral drug infusions to examine the influence of glutamate receptors on striatal output activity. When infused into the dopamine-denervated striatum, the AMPA-kainate receptor antagonist DNQX dose-dependently elicited contralateral rotation and ipsilateral Fos immunoreactivity (Fos-IR) in the globus pallidus, a target nucleus of striatal output. DNQX did not elicit rotation or Fos-IR in unlesioned or partially lesioned rats. In addition, the NMDA receptor antagonist AP-5 failed to induce rotation and had minimal effects on pallidal Fos-IR in lesioned rats. These results suggest a role for striatal AMPA-kainate receptors in the pathology and treatment of Parkinson's disease.