RESUMO
Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic 'low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in dopamine transporter knock-out mice (DAT-/-) compared to wildtype (DAT+/+) mice. Systemic 'low-dose' 3-NP induced a significant impairment in a rotarod task only in DAT-/- mice. Histopathology also demonstrated a significant reduction of the striatal volume (-7%, P < 0.05), neuronal density (-12.5%, P < 0.001) and absolute number estimates of striatal neurons (-11.5%, P < 0.001) in DAT-/- compared to DAT+/+ mice, with increased glial activation, independent of the degree of succinate dehydrogenase inhibition. These findings strengthen the hypothesis for dopamine modulation of excitotoxicity within the nigrostriatal system.
Assuntos
Doenças dos Gânglios da Base/metabolismo , Dopamina/metabolismo , Tolerância a Medicamentos/genética , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras/deficiência , Neostriado/metabolismo , Proteínas do Tecido Nervoso , Vias Neurais/metabolismo , Substância Negra/metabolismo , Animais , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/fisiopatologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Convulsivantes/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Relação Dose-Resposta a Droga , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neostriado/lesões , Neostriado/fisiopatologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Vias Neurais/lesões , Vias Neurais/fisiopatologia , Neurotoxinas/farmacologia , Nitrocompostos , Equilíbrio Postural/efeitos dos fármacos , Equilíbrio Postural/fisiologia , Propionatos/farmacologia , Substância Negra/lesões , Substância Negra/fisiopatologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Reduced stride length characterizes Parkinsonian gait. We aimed to demonstrate that it could be measured simply and reliably in mice by pawprints and used as an index of basal ganglia dysfunction. In C57BL/6 mice, stride length measurements proved to be consistent across measurements and experimenters. It was slightly lower in the hindlimbs and was correlated to femur size and animal velocity. Dopamine depletion by reserpine and striatal dopamine receptor blockade by haloperidol resulted in reduced mean stride length in four limbs. Significant forelimb/hindlimb difference was also observed both in mice with 3-nitropropionic acid (3-NP) induced striatal lesions and in those with MPTP-induced nigral cell loss. Reduction of hindlimb stride length was correlated significantly with the magnitude of cell loss, either in the substantia nigra or in the lateral mid-striatum. Stride length is, therefore, a simple method to obtain an index of motor disorders due to basal ganglia dysfunction in mice.