Morphological and biochemical adaptations to unilateral dopamine denervation of the neostriatum in newborn rats

Abstract

Basal ganglia of adult rats were examined for morphological and biochemical changes resulting from neonatal unilateral dopamine denervation of the striatum with increasing doses of 6-hydroxydopamine (4, 12 and 20 μg). Rotational behaviour induced by apomorphine (0.1 mg/kg) was observed in all rats injected with the high dose (20 μg) and totally absent in those injected with the low dose (4 μg). As assessed with tyrosine hydroxylase immunocytochemistry, the extent of dopamine denervation within the injected striatum was clearly related to the dose injected. In the mesencephalon, losses of tyrosine hydroxylase-immunoreactive cell bodies were proportional to the dose injected and the extent of neostriatal dopamine denervation. This retrograde cell loss predominated in the ventromedial and lateral parts of the substantia nigra pars compacta, with relative sparing of the ventral tegmental area. After the injection of the intermediate (12 μg) and the high (20 μg) doses, a network of thin tyrosine hydroxylase-immunoreactive fibres was visualized in the ventral part of the pars reticulata ipsilateral to the injected striatum, suggesting a neoinnervation of this structure by dopamine axons. After the high dose, the density of serotonin-immunoreactive fibres was enhanced in the anterior half of the lesioned striatum. Associated changes in dopamine and serotonin content and turnover were also documented on both sides, in the striatum and in two output structures of the basal ganglia, the globus pallidus and the substantia nigra. Dopamine content was decreased only on the injected side. After the low dose, equal reductions (−60%) were observed in the anterior striatum and the substantia nigra, whereas a more marked decrease was measured in the anterior striatum (−93%) than in the substantia nigra (−60% to −74%) after the intermediate and high doses. In the globus pallidus, dopamine tissue content was decreased (−51%) only after the high dose. Dopamine turnover was unchanged after the low dose in all structures examined and was increased in the striatum, on the lesioned side only, after the intermediate and high doses. Serotonin content was increased only on the injected side in the anterior striatum (+50% after the low and +92% after the high dose). Serotonin turnover was unchanged on the injected side but increased by +118% and by +81% in the contralateral anterior striatum after the low and high doses, respectively. It was also increased in both substantia nigra after the high dose. In conclusion, morphological changes similar to those described after a bilateral neonatal lesion were observed on the injected side in the model of the unilateral neonatal nigrostriatal dopamine denervation. Biochemical changes were, however, not restricted to the lesioned side. Notably, changes in serotonin turnover developed on the contralateral side. These morphological and biochemical adaptative changes need to be taken into account in considering the mechanisms implicated in the rotional behaviour measured in these animals.