The mesolimbic dopaminergic pathway is more resistant than the nigrostriatal dopaminergic pathway to MPTP and MPP + toxicity: role of BDNF gene expression

Abstract

In the present study we examined the role of BDNF gene expression involved in the differential vulnerability of the nigrostriatal and mesolimbic dopaminergic pathways to environmental damage. The toxins for dopamine (DA) neurons 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP +) were used as pharmacological tools. Results revealed that chronic MPTP treatment produced a significant and irreversible DA depletion in the striatum (ST) as well as a marked decrease in tyrosine-hydroxylase (TH) mRNA level in the substantia nigra (SN). Under these conditions, the endogenous brain-derived neurotrophic factor (BDNF) mRNA level was increased in the SN. Only acute DA reduction was found in the nucleus accumbens (NAc) and TH mRNA level was not affected in the ventral tegmental area (VTA) by MPTP treatment. Further, when MPP + produced a similar extent of DA depletion in the ST and NAc, the TH mRNA level was also decreased while BDNF mRNA level was increased in the SN. The same alterations were not observed in the VTA. Results from the BDNF mRNA regional distribution study revealed that structures in the mesolimbic dopaminergic pathway expressed a more than 2-fold higher basal BDNF mRNA level than structures in the nigrostriatal dopaminergic pathway. Presumably, enhanced BDNF gene expression would help the survival of DA neurons and these findings suggest a better protective mechanism in the mesolimbic pathway. Lastly, direct BDNF infusions to the SN partially protected against MPTP's toxicity on DA neurons in the ST in mice. These results together suggest that a more abundant BDNF mRNA level along the mesolimbic pathway than the nigrostriatal pathway may, at least partially, explain the differential vulnerability of different DA neurons to MPTP and MPP + toxicity.