Alterations in Neurotensin‐ and Bombesin‐like Immunoreactivity in MPTP‐Treated Micea

Abstract

l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes destruction of nigrostriatal dopamine (DA) neurons and subsequent symptoms resembling Parkinson's disease (PD) in humans and subhuman primates. The MPTP-treated mouse has recently been proposed as an animal model of PD.' In a previous study, we demonstrated decreases in the regional brain concentrations of the neuromodulatory peptides neurotensin (NT) and bombesin (BOM) in human patients with idiopathic PD.' One goal of these studies was to determine whether this murine model is an appropriate model of PD with respect to neuropeptide alterations. Adult, male, Swiss-Webster mice were injected daily with MPTP (30 mg/kg, ip) for 5 consecutive days. The mice were killed on day 10, the brains rapidly removed, dissected into 12 regions, and frozen. Brain regions were extracted and assayed for NT and BOM by sensitive and specific radioimmunoassays previously described in detail.'.' When compared to controls, the concentration of NT was decreased in the frontal cortex (p < 0.01), caudate (p < Om), and preoptic area (p < 0.02) of the MPTP-treated animals. An increase in BOM concentration was found in the amygdala (P < 0.04), whereas a decrease in the concentration of this peptide was observed in the preoptic area (P < 0.05) of the MPTP-treated animals (TABLE 1). Specificity of the DA neuronal degeneration was verified by reversal-phase HPLC assay5 of caudate samples for DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) (FIG. 1). Caudate DA, DOPAC, and HVA concentrations were decreased to 12% (p 4 0.01), 28% (p 4 0.01), and 42% (p < 0.01) of control, respectively. A decrease in 5-HT concentration to 69% of control (p < 0.02) was found, while 5-HIAA exhibited a nonsignificant increase to 118% of control, indicating a slight increase in 5-HT turnover. Although substantial depletion of striatal DA was observed in the MPTP-treated mice, the brain, regions exhibiting changes in NT and BOM concentration differed substantially from those demonstrated in human idiopathic PD (IPD), where a decrease in NT was observed in the hippocampus and decreases in BOM concentration were found in the caudate and globus pallidus. The young mature MPTP-treated mouse would therefore appear not to be a satisfactory model of human PD with respect to neuropeptide