05, P < 0.0001; Fig. 7A). Tukey post hoc analysis revealed that the severe lesion was significantly different from the intermediate lesion (P < 0.05) and highly significantly different from the mild lesion (P < 0.0001), while the intermediate lesion was significantly different from the mild lesion (P < 0.05). Apomorphine-induced rotation was also able to differentiate between the three subgroups (Group, F2,33 = 15.09, P < 0.0001; Fig. 7B). The post hoc analysis revealed that the severe lesion was significantly different from the intermediate lesion (P < 0.05) and
highly significantly different from the mild lesion (P < 0.0001), while the intermediate lesion was significanly different from the mild lesion (P < 0.05). Amphetamine
rotation was clearly less informative and could only differentiate between the animals with a mild lesion and those with > 60% striatal denervation (Group, F2,33 = 10.69, selleck chemicals P < 0.0001; Fig. 7C); Tukey post hoc analysis revealed that the mild lesion was significantly different Smad inhibitor from both the intermediate and the severe lesions (P < 0.001 and P < 0.05, respectively). By contrast, neither the stepping test nor the cylinder tests were able to distinguish between any of the lesion types (Group, F2,33 = 2.08, P = 0.15, n.s; Group, F2,27 = 1.31, P = 0.29, n.s, respectively; Fig. 5D and E). A subset of seven severely lesioned mice was followed long-term in four of the tests that showed profound deficits at the early post-lesion time-point (6–7 weeks), and were compared to a group of seven intact control animals (Fig. 8A–D). In all four tests the two groups showed stable
performance over the entire test period (20–23 weeks), and the lesioned and intact mice performed significantly different from one another in all four tests, including the corridor test (Group, χ21,48 = 827.14, P < 0.0001; Fig. 8A), apomorphine-induced rotation (Group, χ21,48 = 159.69, P < 0.0001; Fig. 8B), amphetamine-induced rotation (Group, χ21,48 = 26.91, P < 0.0001; Fig. 8C) and the stepping test (Group, χ21,36 = 208.26, P < 0.0001; Fig. 8D). There was no significant effect Rutecarpine of time measured in any of the behavioural tests, thus confirming the stability performance in both the intact and lesioned groups (data not shown). The results show that intranigral 6-OHDA lesions can be used to induce profound loss of midbrain dopaminergic (DAergic) neurons, accompanied by extensive denervation of the striatum and behavioural impairments in a range of drug-induced and spontaneous motor tests. Based on the extent of striatal TH+ denervation we allocated the mice into three subgroups, exhibiting severe, intermediate and mild lesions of the mesostriatal pathway. From the behavioural impairments seen in these subgroups, it was possible to predict the severity of the lesion, i.e.