Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms u nderlying the generation of dyskinesia following repeated L-3,4-dihydroxyph enylalanine (L-DOPA) or dopamine agonist administration in Parkinson's dise ase remain unknown. However, de novo administration of bromocriptine or lis uride to either 1-methyl-4-phenyl1,2,3,6 tetrahydropyridine-lesioned primat es or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenke phalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenk ephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A(1-17) and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output path ways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's di sease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal gangli a circuitry into anatomically discrete parallel circuits, we investigated a lterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. Th is became markedly enhanced with repeated treatment. We have previously cha racterized the pharmacology of this enhanced response and have suggested th at it is a useful model for the elucidation of the cellular and molecular m echanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In co ntrast to L-DOPG de novo administration of bromocriptine (1 or 5 mg/kg, b.d ., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animal s, PPE-A expression was elevated rostrally and dorsally, while PPE-B expres sion was reduced in the striatum at all rostrocaudal levels. Repeated L-DOP A administration was accompanied by elevations in striatal PPE-B mRNA level s and a further elevation, above lesion-induced levels, in PPE-A expression . This further elevation was restricted to the dorsolateral striatum. Howev er, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B le vels may, through decreasing GABA and glutamate release, respectively, in o utput nuclei of the basal ganglia, play a role in the development of L-DOPA - and dopamine-agonist induced dyskinesia in Parkinson's disease. These stu dies suggest that anti-parkinsonian treatments which are not associated wit h an elevation in PPE-B and/or normalize elevated PPE-A precursor expressio n, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor ag onists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson 's disease. (C) 1999Academic Press.