Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

GABA and enkephalin-utilizing efferents from the striatum to the external s egment of the pallidal complex (GPe) are thought to be overactive in Parkin son's disease (PD). This overactivity is generally held to play a major rol e in the genesis of parkinsonian symptoms, which are thought to appear when dopaminergic neuronal death exceeds a critical threshold. Little is known, however, regarding the activity of this pathway during disease progression and more particularly, prior to the emergence of parkinsonian symptoms. In order to test the hypothesis that an upregulation of striatal preproenkeph alin-A (PPE-A) mRNA levels occurs before the appearance of parkinsonian mot or disabilities, the present study assessed PPE-A mRNA expression and stria tal dopamine (DA) content following a chronic 1-methyl-4-phenyl-1,2,3,6-tet rahydropyridine (MPTP) administration protocol in monkeys that produces a p rogressive parkinsonian state. Groups ranged from normal to full parkinsoni an through asymptomatic lesioned monkeys. The key finding of this study is that PPE-A expression is already upregulated in asymptomatic-lesioned monke ys showing a marked DA depletion (56%), Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased P PE-A mRNA expression observed in asymptomatic, but DA-depleted animals, sup ports our initial hypothesis of such an upregulation occurring before the a ppearance of parkinsonian motor disabilities. Furthermore, when considered with recent electrophysiological and histochemical data, these findings que stion the functional significance of upregulated enkephalin transmission in the indirect striatopallidal pathway. (C) 2001 Academic Press.