EFFECTS OF L-DOPA ON PREPROENKEPHALIN AND PREPROTACHYKININ GENE-EXPRESSION IN THE MPTP-TREATED MONKEY STRIATUM

The cellular expression of the genes encoding the neuropeptides enkeph alin and substance P were examined in the caudate nucleus and putamen of parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-tr eated cynomolgus monkeys by in situ hybridization using radioactive an tisense oligonucleotides coupled with computer-assisted image analysis . Behavioural evaluation of the animals revealed two levels of motor i mpairment; one group moderately impaired and the other severely disabl ed. A marked increase in the cellular content of preproenkephalin A me ssenger RNA was observed in medium-sized (106 +/- 9 mu m(2)) cells in the caudate-putamen of all MPTP animals when compared with controls, t he increase being greatest in the most severely impaired animals. By c ontrast, a marked reduction in the cellular abundance of preprotachyki nin gene expression was detected in striatal cells (101 +/- 16 mu m(2) ) of these same MPTP animals. These changes in neuropeptide gene expre ssion were not associated with a change in the density (approximately 10 cells per mm(2)) of messenger RNA-expressing cells. L-DOPA treatmen t of two of the severely-impaired MPTP monkeys resulted in a dissociat ion of expression of these two genes: the cellular abundance of prepro enkephalin A remained elevated whilst preprotachykinin levels were nor malized and comparable with controls. No change in the cellular abunda nce of preprotachykinin messenger RNA was observed in cells of the ins ular cortex or a small discrete population of large cells (208 +/- 27 mu m(2)) in the ventral putamen. These results demonstrate that MPTP t reatment of primates results in a marked potentiation in preproenkepha lin messenger RNA coupled with an attenuation in preprotachykinin mess enger RNA in the dopamine-denervated caudate-putamen. L-DOPA therapy g iven on an intermittent schedule reverses the decrease in preprotachyk inin messenger RNA, but fails to reverse the increase in preproenkepha lin messenger RNA in the same animal. These observations suggest that a dissociation of the activity of these two neuropeptide systems may u nderlie the improvement in motor skill that accompanies dopamine repla cement therapy and that this dissociation may well be instrumental in the long-term complications associated with L-DOPA therapy.