Received for publication April 6, 2005.
Revised June 2, 2005.
Accepted for publication June 2, 2005.

The effects of a selective dopamine D2 receptor agonist on behavioral and pathologic outcome in MPTP-treated squirrel monkeys

Abstract

In this study we investigated antiparkinsonian activity of the novel highly selective dopamine D2 receptor agonist sumanirole as compared to two clinically effective dopaminergic therapies in the MPTP primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, L-DOPA plus carbidopa (L-DOPA), ropinirole, or sumanirole over a duration of eight weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome as compared to vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole while L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was L-DOPA>sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with L-DOPA treatment but were not observed in sumanirole, ropinirole or placebo treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor FosB were most significantly increased in the striatum of L-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to L-DOPA without the behavioral and morphological consequences of the latter.

Key words: L-DOPA, Parkinson's Disease, deltafosB, dyskinesia, ropinirole, sumanirole