Neurotensin receptors and dopamine transporters: Effects of MPTP lesioningand chronic dopaminergic treatments in monkeys

The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) rece ptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicula ris) was investigated. The MPTP lesion induced a marked depletion of DA (90 % or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [I-125]NT and the NT antagonist bind ing sites labeled with [H-3]SR142948A decreased by half in the caudate-puta men of MPTP-monkeys. In addition, the densities of [I-125]NT and [H-3]SR142 948A binding sites markedly decreased (-77 and -63%, respectively) in the s ubstantia nigra of MPTP-monkeys. Levocabastine did not compete with high af finity for [I-125]NT binding in the monkey cingulate cortex, suggesting tha t only one class of NT receptors was labelled in the monkey brain. An exten sive decrease of [H-3]GBR12935 DAT binding sites (-92% vs. Control) was obs erved in. the striatum of MPTP-monkeys and an important loss of DAT mRNA (- 86% vs. Control) was observed in substantia nigra. Treatments for 1 month w ith either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergo line (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT an d DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this' nucl eus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervati on, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density. (C) 1999 Wiley-Liss, Inc.