Indeed, dopamine-grafted rats receiving slow-release nimodipine pellets showed significantly less severe levodopa-induced dyskinesias at the latest time-point examined when compared with rats receiving dopamine grafts plus vehicle pellets (dyskinesia severity scores: dopamine-grafted = 5.06 ± 1.29, dopamine-grafted + nimodipine =1.33 ± 0.59; P = 0.02; Fig. 5A). In sham-grafted parkinsonian rats, maintaining dendritic PS 341 spine density with nimodipine pellets resulted in significantly lower levels of levodopa-induced dyskinesias compared with sham-grafted rats receiving vehicle pellets at early (dyskinesia severity scores: sham-grafted = 8.54 ± 1.58,

sham-grafted + nimodipine = 1.15 ± 0.22; P =0.005) and middle (sham-grafted = 9.88 ± 1.05, sham-grafted + nimodipine = 4.93 ± 1.44; P = 0.013)

time-points post-grafting (Fig. 5B). However, unlike dopamine-grafted rats where dyskinesia prevention was maintained in rats with preserved spine density, repeated dosing of levodopa in the absence of a graft resulted in a INCB018424 datasheet loss of this ‘buffering’ capacity over time (late time-point dyskinesia severity scores: sham-grafted = 10.29 ± 1.41, sham-grafted + nimodipine = 7.68 ± 1.67; P = 0.176). Analysis of levodopa-induced dyskinesias in non-pelleted, acutely drug-tested rats found that there is no apparent nimodipine–levodopa drug–drug interaction that impacts behavioral indices used in the current study. Indeed,

none of the nimodipine doses tested, ranging from 10-fold less to approximately 30-fold higher than the dose employed in the slow-release pellets, directly interfered with or potentiated levodopa-induced dyskinesias (6 mg/kg levodopa: 0.08 mg/kg nimodipine P = 1.0, 0.8 mg/kg nimodipine P = 0.836, 8 mg/kg nimodipine P = 0.871; 8 mg/kg levodopa: 0.08 mg/kg nimodipine P = 0.944, 0.8 mg/kg nimodipine P = 0.761, 8 mg/kg nimodipine P = 0.382; 12.5 mg/kg levodopa: 0.08 mg/kg nimodipine P = 0.574, 0.8 mg/kg nimodipine P = 0.908, 8 mg/kg nimodipine P = 0.492, 20 mg/kg nimodipine P = 0.856; Fig. 6). Neither nimodipine treatment nor dopamine grafting appeared to have any overall significant effect on performance in the MG 132 cylinder task (F2,11 = 1.843, P = 0.204) with the moderate number of dopamine neurons grafted in this study. At all time-points examined, no significant effect of dopamine grafting plus vehicle pellets was observed, with sham-grafted and dopamine-grafted rats showing no difference in forelimb use to one another (P = 0.978). While dopamine-grafted rats receiving nimodipine pellets trended towards improved performance, this was not statistically significant at any of the time-points observed (P = 0.203; Fig. 7). As we have reported previously, sham-grafted rats showed little-to-no expression of the graft-induced forepaw TPD.