Experimental Modeling of Functional Deficiency of the Nigrostriatal Dopaminergic System in Mice

Abstract

The dopaminergic nigrostriatal system of the brain is a key component in controlling motor behavior. The bodies of dopaminergic neurons are located in the compact zone of the substantia nigra and their axons, forming the nigrostriatal tract, project to the striatum. The aim of the present work was to develop an experimental model of functional deficiency of the dopaminergic neurons of the nigrostriatal system with no impairment to motor behavior, i.e., the presymptomatic stage of parkinsonism. The model was created in mice by administration of single subcutaneous injections of low doses (12 mg/kg) of 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is converted to MPP+ in the brain, this being a neurotoxin for dopaminergic neurons. These experiments showed that 14 days after administration of MPTP the animals a) lacked any impairment to motor behavior; b) had no decrease in the dopamine level or any dopamine neuron degeneration in the substantia nigra; c) showed significant reductions in dopamine levels in the striatum due to degeneration of half of its dopaminergic fibers. The absence of changes in motor behavior in the presence of significant changes in dopamine metabolism and structural damage to dopaminergic axons in the striatum provides evidence for the activation of compensatory mechanisms in the brain. Thus, we have developed an experimental model of the presymptomatic stage of parkinsonism, which is characterized by degeneration of the axons of dopaminergic neurons in the striatum with no changes in the bodies of these neurons in the substantia nigra; this model will be used for further studies of compensatory mechanisms.