INTERACTION OF VESICULAR MONOAMINE TRANSPORTER 2 (VMAT2) AND NEUROMELANIN PIGMENT AMONG THE MIDBRAIN DOPAMINERGIC NEURONS, IN MAN

Neuromelanin (NM) pigment accumulates with age in catecholaminergic neurons in man, and the ventral substantia nigra dopaminergic neurons that are the most vulnerable to degeneration in Parkinson's disease (PD) contain the greatest amount of this pigment. In vitro data indicate that NM pigment is formed from the excess cytosolic catecholamine that is not accumulated into synaptic vesicles via the vesicular monoamine transporter2 (VMAT2). Using semi-quantitative immunohistochemical methods in human postmortem brain, we sought to examine the relationship between the contents of VMAT2 and NM pigment. The immunostaining intensity (ISI) was measured for VMAT2 in two regions of the midbrain dopaminergic cell complex. The ISI of the cells was related to the density of NM pigment within the cells. We also measured the ISI for tyrosine hydroxylase (TH) and examined the noradrenergic neurons in the locus coeruleus (LC). In brains 22-65 years of age: 1) ventral substantia nigra neurons had the lowest VMAT2 ISI of all neurons in the midbrain cell complex, whereas over 2-fold higher levels are found in most ventral tegmental area neurons; 2) there was an inverse relationship between VMAT2 ISI and neuromelanin pigment in the midbrain dompaminergic neurons; 3) neurons with the highest VMAT2 ISI resided in the LC; 4) neurons with high VMAT2 ISI also had high TH ISI; and 5) in the newborn brain, which has not yet accumulated neuromelanin pigment in the aminergic neurons, the regional distribution of VMAT2 and TH-ISI was similar to that found in the adult brain. These data support the hypothesis that among the midbrain dopaminergic neurons, the ventral substantia nigra dopamine neurons accumulate the highest levels of NM pigment because they have the lowest levels of VMAT2, which thereby renders them especially vulnerable to degeneration in PD