The effect of l-DOPA and carbidopa treatment on the survival of rat fetal dopamine grafts assessed by tyrosine hydroxylase immunohistochemistry and [ 3H]mazindol autoradiography

Abstract

The effect of treatment with l-3,4-dihydroxyphenylalanine ( l-DOPA) and carbidopa for five weeks on the survival of rat fetal dopaminergic ventral mesencephalon cells implanted into denervated striatum of rats with unilateral 6-hydroxydopamine nigrostriatal lesions was assessed. Rat receiving unilateral nigral 6-hydroxydopamine lesions followed by sham striatal grafts (Groups A and B) showed no recovery of (+)-amphetamine- or apomorphine-induced motor asymmetry. Rats in Group B (receiving treatment with l-DOPA and carbidopa) showed an increase in apomorphine-induced contralateral rotation and stereotypy. Animals receiving unilateral nigral 6-hydroxydopamine lesions followed by fetal striatal dopamine grafts (Groups C and D) showed complete recovery of (+)-amphetamine-induced rotation and a decrease of apomorphine-induced contralateral rotation. Treatment of animals in Groups B and D with l-DOPA (200 mg/kg per 24 h) and carbidopa (25 mg/kg per 24 h) by mouth for five weeks had no effect on the behavioural response to (+)-amphetamine. In the 6-hydroxydopamine-lesioned animals there was loss of tyrosine hydroxylase-immunoreactive cells in substantia nigra and ventral tegmental area of 97% and to 66%, respectively, compared to the intact side. The number and morphology of tyrosine hydroxylase-immunoreactive cells in the intact substantia nigra and ventral tegmental area was not altered by treatment with l-DOPA and carbidopa. In the 6-hydroxydopamine-lesioned striatum of rats receiving a sham graft (Group A) or a sham graft and treatment with l-DOPA and carbidopa (Group B) there were no tyrosine hydroxylase-positive cells or fibres visible. In the striatum of animals with a unilateral 6-hydroxydopamine lesion receiving a fetal nigral graft (Group C), tyrosine hydroxylase-positive cells were present showing fibre outgrowth. The administration of l-DOPA and carbidopa to 6-hydroxydopamine-lesioned rats with a fetal nigral graft (Group D) had no effect on the volume of the graft or the number of tyrosine hydroxylase-positive cells. Specific [ 3H]mazindol binding to striatal slices was reduced by 90% in the lesioned striatum of animals receiving sham grafts compared with the intact side (Group A); this was unaffected by the administration of l-DOPA and carbidopa (Group B). In the striatum of rats receiving implantation of fetal nigral cells into the previously denervated striatum (Group C) specific [ 3H]mazindol binding was up to 64% of that found on the intact side; again, this was not diminished by treatment with l-DOPA and carbidopa (Group D). The density of specific [ 3H]mazindol binding in the grafts and in the intact striatum was higher in animals treated with l-DOPA and carbidopa. These results suggest that this chronic treatment with l-DOPA and carbidopa does not impair the survival of dopamine cells in rat fetal nigral grafts as demonstrated by tyrosine hydroxylase immunohistochemistry, or their fibre outgrowth as revealed by [ 3H]mazindol autoradiography.