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

Abstract

The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) 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 [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed 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 with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and 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 nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.

Relevance of different striatal markers in assessment of the MPP+‐induced dopaminergic nigrostriatal injury in rat

“…In our MPP + rat model we have chosen only to study the levels of DA and its metabolites. In accordance with Goulet et al . (1999), the depletion of DA and its metabolites were matched with the reduction of the membrane DAT expression measured in striatal membrane homogenates and with our reference in vivo marker.…”

“…2000). Interestingly, many studies underlined that the markedly reduced DAT binding sites in striatal membranes homogenates could be suitable as a quantitative marker of dopaminergic denervation in the striatum (Goulet et al . 1999; Fornai et al .…”

l-Dopa treatment abolishes the numerical increase in striatal dopaminergic neurons in parkinsonian monkeys

“…Baseline parkinsonian score and antiparkinsonian efficacy of L-dopa treatment in these monkeys were evaluated using a disability scale for MPTP-treated monkeys (Hadj Tahar et al, 2000). Extent of DA denervation was assessed by measuring striatal DA concentrations with high performance liquid chromatography (HPLC) (Goulet et al, 1999) and by measuring DAT specific binding activity with radioligand autoradiography using 125 I-RTI-121 (3b-(4-125 I-iodophenyl)tropane-2b-carboxylic acid isopropyl ester. These procedures were described in detail eselwhere (Calon et al, 2002;Morissette et al, 2006a,b).…”

Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys

“…The supernatants were kept at −80°C in small polyethylene tubes until time of assay, while the pellets were solubilized in 100 μl of 0.1 M NaOH for determination of protein content. The concentration of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA), as well as 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), in the caudate nucleus and putamen were measured by high-performance liquid chromatography with electrochemical detection, according to our previously published procedures (Goulet et al, 1999;Morissette et al, 2006).…”