THE MESOLIMBIC DOPAMINERGIC PATHWAY IS MORE RESISTANT THAN THE NIGROSTRIATAL DOPAMINERGIC PATHWAY TO MPTP AND MPP(- ROLE OF BDNF GENE-EXPRESSION() TOXICITY )

In the present study we examined the role of BDNF gene expression invo lved in the differential vulnerability of the nigrostriatal and mesoli mbic dopaminergic pathways to environmental damage. The toxins for dop amine (DA) neurons 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP ) and 1-methyl-4-phenylpyridinium (MPP(+)) were used as pharmacologica l tools. Results revealed that chronic MPTP treatment produced a signi ficant and irreversible DA depletion in the striatum (ST) as well as a marked decrease in tyrosine-hydroxylase (TH) mRNA level in the substa ntia nigra (SN). Under these conditions, the endogenous brain-derived neurotrophic factor (BDNF) mRNA level was increased in the SN. Only ac ute DA reduction was found in the nucleus accumbens (NAc) and TH mRNA level was not affected in the ventral tegmental area (VTA) by MPTP tre atment. Further, when MPP(+) produced a similar extent of DA depletion in the ST and NAc, the TH mRNA level was also decreased while BDNF mR NA level was increased in the SN. The same alterations were not observ ed in the VTA. Results from the BDNF mRNA regional distribution study revealed that structures in the mesolimbic dopaminergic pathway expres sed a more than 2-fold higher basal BDNF mRNA level than structures in the nigrostriatal dopaminergic pathway, Presumably, enhanced BDNF gen e expression would help the survival of DA neurons and these findings suggest a better protective mechanism in the mesolimbic pathway, Lastl y, direct BDNF infusions to the SN partially protected against MPTP's toxicity on DA neurons in the ST in mice. These results together sugge st that a more abundant BDNF mRNA level along the mesolimbic pathway t han the nigrostriatal pathway may, at least partially, explain the dif ferential vulnerability of different DA neurons to MPTP and MPP(+) tox icity.