Expression of striatal preprotachykinin mRNA in symptomatic and asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys is related to parkinsonian motor signs.
Striatal preprotachykinin (PPT) gene expression and [(3)H]mazindol binding were examined in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Some animals (n = 5) became moderately to severely parkinsonian after receiving large doses of MPTP over 9-30 d and remained symptomatic for a relatively short time (3 weeks to 3 months; acutely symptomatic group). A second group of animals (n = 5) received low doses of MPTP (1.5-12 months), developed cognitive impairments but displayed no gross motor deficits (asymptomatic group), and were killed 3-12 months after their final dose of MPTP. Other animals became moderately to severely parkinsonian after receiving escalating doses of MPTP (>6 months; n = 4) or high doses of MPTP (<1 month; n = 1) and remained symptomatic for 2.5-5.75 years (chronically symptomatic group). All MPTP-treated animals had extensive losses of [(3)H]mazindol binding in dorsal striatal sensorimotor regions with asymptomatic animals generally having a lesser degree of damage. However, PPT mRNA levels differed sharply among treatment groups. Symptomatic animals (acutely and chronically parkinsonian) had significantly decreased PPT mRNA levels in most striatal regions. In asymptomatic animals, PPT mRNA expression was not significantly different from that measured in control animals, despite decreases in [(3)H]mazindol binding in some striatal regions of similar magnitude to those observed in symptomatic animals. These observations suggest that PPT gene expression may be directly related to expression of parkinsonian motor symptomatology regardless of duration of MPTP exposure, duration of the parkinsonism, or extent of dopamine denervation. These results imply that the direct striatal output circuit may have a greater contribution to expression of parkinsonian symptomatology than proposed previously.
Wade
T V
TV
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Schneider
J S
JS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001345:Autoradiography; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D017403:In Situ Hybridization; D008251:Macaca; D008297:Male; D008454:Mazindol / Q000493:pharmacokinetics; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D011237:Predictive Value of Tests; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*; D012720:Severity of Illness Index; D015320:Tachykinins / Q000096:biosynthesis* / Q000235:genetics; D014316:Tritium
D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D014316:Tritium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008454:Mazindol