preproenkephalin and entacapone

Coadministration of entacapone with levodopa attenuates motor complications in experimental models of Parkinson's disease. The mechanisms underlying entacapone effects are unknown. We investigated the effect of entacapone, on: long-duration response (LDR) to levodopa, levodopa-induced postsynaptic pharmacodynamic mechanisms and molecular changes in hemiparkinsonian rats. 6-Hydroxydopamine-unilaterally lesioned rats were treated with levodopa (25 mg/kg)+vehicle; levodopa+entacapone (30 mg/kg) or saline, twice daily for 22 days. The LDR and the apomorphine-induced rotations were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin and dopamine D-3 receptor mRNAs, subthalamic cytochrome oxidase mRNA and nigral glutamic acid decarboxylase mRNA. Entacapone potentiated the LDR but did not modify either the apomorphine-induced rotational behavior or the molecular changes. Our results suggest that the effects of entacapone on levodopa-induced motor response are not mediated by postsynaptic mechanisms and that administration of entacapone is not able to normalize the molecular alterations induced by levodopa in the basal ganglia.

Topics: Animals; Antiparkinson Agents; Apomorphine; Brain; Catechols; Corpus Striatum; Dynorphins; Electron Transport Complex IV; Enkephalins; Gene Expression; Glutamate Decarboxylase; Immunohistochemistry; In Situ Hybridization; Levodopa; Male; Motor Activity; Nitriles; Parkinsonian Disorders; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; RNA, Messenger; Substantia Nigra; Subthalamus

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agents; Dyskinesia, Drug-Induced; Enkephalins; Female; In Situ Hybridization; Levodopa; Macaca fascicularis; Male; Nitriles; Oligonucleotide Probes; Protein Precursors; Receptors, Purinergic P1; RNA, Messenger; Tachykinins