〔Abstract〕 Objective To compare the functional changes of neurotransmitters in the dopamine(DA) system of rats lesioned by 6-hydroxydopamine in unilateral medial forebrain bundle(MFB) and unilateral striatum after 4 weeks of modeling. Methods Adult male Sprague-Dawley rats(n=62) were divided randomly into four groups: single-site model(one site striatal lesion model,n=18), four-site model(four sites striatal lesion model,n=18), MFB model(MFB lesion model,n=18) and a sham operated control group(n=8). Immunohistochemical tyrosine hydroxylase(TH) staining was used to calculate the loss rate of positive DA neurons. The functional changes of dopamine transporters(DAT)and D2 receptors in rat models of four groups were detected by radioligand-receptor binding assayin vitro, behavioral test and small-animal PET. Results Immunohistochemical staining results of TH at 1-lesion, 4-lesion and MFB model showed that the TH-positive cell loss rates of the lesion side in three models were 19.1%, 84.7% and 97.1%, respectively, indicating that the model was successfully constructed. The results of DAT/D2 receptor functions in the three models showed that, compared with the sham operated control group, the DAT binding ratio of radioactivity on the lesion side of 1-lesion, 4-lesion and MFB model significantly decreased(P<0.05,P<0.05 andP<0.01). The DAT binding ratio of radioactivity on the lesion side was compared among 1, 4 lesion and MFB model. It was found that the decrease degree of MFB model was significantly higher than that of the previous two models(P<0.01), and the decrease degree of 4-lesion model was significantly higher than that of 1-lesion model(P<0.05). Compared with the sham operated control group, the D2 receptor binding ratio of radioactivity on the lesion side of 1-lesion and 4-lesion model significantly decreased(P<0.05), and there was no significant difference in the degree of decrease between the two models, but the D2 receptor binding ratio of radioactivity on the lesion side of MFB model significantly increased(P<0.05). There was no difference in the distribution of DAT/D2 receptor on the lesion side and the normal side of the sham operated control group. Methamphetamine caused ipsilateral rotations to the lesion side in all models. There were no significant differences in methamphetamine-induced rotation among 1-lesion, 4-lesion and MFB models. Bromocriptine caused ipsilateral rotations to the lesion side in 1-lesion and 4-lesion models but contralateral rotations in MFB model. There were no significant differences in bromocriptine-induced rotation between 1-lesion and 4-lesion models. The results of stepping test showed the motion initiation time of the lesion side was significantly longer than that of the normal side, the stepping length of the lesion side was significantly shorter than that of the normal side, and the adjusting steps of the lesion side was significantly less than that of the normal side(P<0.001), but there was no significant difference of the lesion side in the initiation time, stepping length, and adjusting steps among the three groups of models. Conclusion The striatal lesion and MFB lesion models showed different pathophysiological processes in terms of DA neurotransmitter functions and behavior. The MFB lesion model can mimic primary Parkinson′s disease, while the striatal lesion model is similar to some Parkinson syndromes.