Toxicity of MPTP on neurotransmission in three mouse models of Parkinson's disease

Abstract

Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder after Alzheimer's disease. PD is mainly characterized by a selective degeneration of the dopaminergic neurons in the substantia nigra. Also, it is observed imbalances in some nondopaminergic systems, including the serotonergic system. Serotonergic dysfunction appears to play a role in some parkinsonian symptoms, including motor function, L-dopa-induced dyskinesia, mood, psychosis, and constipation. The fact that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a parkinsonian syndrome was discovered in 1982 and has been used extensively and successfully in various mammalian species, including monkeys and mice, to produce an experimental model of PD. Three common dosing regimens of the MPTP-induced mice model of PD were compared on dopaminergic neurotransmission and serotonin levels in various brain regions. Results showed that tyrosine hydroxylase activity and dopaminergic transporter density were reduced in striatum and substantia nigra of mice and that this reduction was dependent on the cumulative dose of MPTP injected. Furthermore, for the three protocols, a decrease of dopamine (DA) level was observed in striatum, associated with a significant diminution of DA concentration in frontal cortex only for the chronic treatment. Moreover, a decrease of serotonin level was observed in midbrain and hippocampus of acute and sub-acute intoxicated-mice. In all, the results suggested that dosing regimen should be carefully pre-considered. Furthermore, the acute and sub-acute MPTP protocols represent good models of early, subclinical stages of PD, ideal in the development of neuroprotective strategies.