Rasagiline enhances L-DOPA-induced contralateral turning in the unilateral 6-hydroxydopamine-lesioned guinea-pig.

ABSTRACT

The modification of L-3,4-dihydrooxyphenylalanine- (L-DOPA-) induced turning response by the new selective monoamine oxidase type B (MAO-B) inhibitor rasagiline was studied in guinea-pigs bearing a unilateral 6-hydroxydopamine-induced lesion in the substantia nigra. In an initial experiment, it was established that contralateral turning is induced in lesioned guinea-pigs in response to apomorphine (18 mg/kg i.p.) and L-DOPA/carbidopa (15/3.5 mg/kg i.p.), while ipsilateral turning is induced by S(+)-methamphetamine (7 mg/kg i.p.). The effect of rasagiline was studied in a chronic treatment regimen, in which animals were treated with rasagiline (0.05 mg/kg s.c.) or saline s.c. daily commencing 2 weeks after lesioning, and L-DOPA/carbidopa (41 mg/kg) was administered once daily for 21 days. Only guinea-pigs with 95% or more depletion of striatal dopamine were included in this study. Guinea-pigs treated with rasagiline had a significantly increased intensity and duration of turning in response to L-DOPA (P <0.05 by repeated measures ANOVA) over the 21-day period. On day 21, turning averaged 806+/-105 (n=10) vs 442+/-123 (n=11) turns per 180 min for rasagiline and vehicle treated animals, respectively (P <0.05); turning duration half-time averaged 81+/-15.4 (n=10) as opposed to 33+/-7.6 (n=11) min for rasagiline and vehicle treatments (P <0.01). Concentration of dopamine in intact striatum was significantly increased (69.3+/-2.1 and 60.3+/-2.4 pmol/mg tissue for rasagiline and vehicle, P <0.05) and levels of dihydroxyphenylacetic acid and homovanillic acid were decreased by the rasagiline treatment. Activity of brain MAO-B was 8.6+/-2.9% and MAO-A was 71+/-1.5% that of control in rasagiline-treated animals. Chronic, selective inhibition of MAO-B by rasagiline potentiated L-DOPA-induced turning in this rodent model.