Chronic l-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra

Abstract

The aim of the study was to determine whether the dopamine (DA) precursor l-DOPA attenuates parkinsonian-like symptoms produced by the ubiquitin-proteasome system inhibitor lactacystin. Wistar rats were injected unilaterally with lactacystin (2.5μg/2μl) or 6-OHDA (8μg/2μl) into the substantia nigra (SN) pars compacta. Four weeks after the lesion, the animals were treated chronically with l-DOPA (25 or 50mg/kg) for two weeks. During l-DOPA treatment, the lactacystin-treated rats were tested for catalepsy and forelimb asymmetry. Rotational behavior was evaluated after apomorphine (0.25mg/kg) and l-DOPA in both PD models. After completion of experiments, the animals were killed and the levels of DA and its metabolites in the striatum and SN were assayed. We found that acute l-DOPA administration effectively decreased catalepsy and increased the use of the compromised forelimb in the cylinder test. However, the lactacystin group did not respond to apomorphine or acute l-DOPA administration in the rotational test. Repeated l-DOPA treatment produced contralateral rotations in both PD models, but the number of rotations was much greater in the 6-OHDA-lesioned rats. Both toxins markedly (>90%) reduced the levels of DA and its metabolites in the striatum and SN, while l-DOPA diminished these decreases, especially in the SN. By demonstrating the efficacy of l-DOPA in several behavioral tests, our study confirms the usefulness of the lactacystin lesion as a model of PD. However, marked differences in the rotational response to apomorphine and l-DOPA suggest different mechanisms of neurodegeneration evoked by lactacystin and 6-OHDA.