A mitochondrial complex-I inhibitor,
rotenone was unilaterally infused into the substantia nigra pars compacta (SNpc) or median forebrain bundle (MFB) to create hemiparkinsonian animal models and investigated spontaneous and drug-induced stereotypic rotations, as well as certain postural behaviors in Sprague-Dawley rats. Animals infused intranigrally, but not intra-MFB, with
rotenone exhibited spontaneous contralateral rotations immediately after recovery from
anesthesia. Head position bias and elevated body swing test showed insignificant contralateral bias in animals with nigral damage but a significant ipsilateral bias in MFB-lesioned rats. General motor activity of the animals was reduced in both the groups as indicated by reduced performance on a Plus-Maze. Intranigrally,
rotenone-infused animals exhibited progressive ipsilateral rotations when challenged with
d-amphetamine on the 7th, 14th, 21st, and 28th days or with
apomorphine on 9th, 16th, 23rd, and 30th days. However, animals that received
rotenone in MFB exhibited ipsilateral or contralateral rotations when challenged respectively with
d-amphetamine or
apomorphine only in the 5th week (28th and 30th days). Stereotaxic administration of
rotenone into SNpc or MFB caused a significant loss of
dopamine in the ipsilateral striatum (>80% in SNpc; >95% in MFB), when assayed employing an HPLC equipped with electrochemical detector on the 32nd day. Neuronal loss in SNpc was confirmed in coronal sections stained with
cresyl violet and revealed extension of lesion towards SN pars reticulata, in SNpc-infused animals. Our results demonstrate that
rotenone-induced neurodegeneration is a slow, yet progressive process similar to that in
idiopathic Parkinson's disease and unlike that observed in other classical
neurotoxin-mediated lesions which are abrupt and developed in few hours to days. Thus, intranigral or intra-MFB infusion of
rotenone could be used for producing hemiparkinsonian animal models in rats. These findings further suggest that, while both
d-amphetamine and
apomorphine-induced stereotypic rotations could be used as a valuable behavioral assay procedure to test novel drugs against
Parkinson's disease, yet apomorpine-induced contralateral bias in turning is a reliable
indicator of specific destruction in nigrostriatal pathway and development of postsynaptic
dopamine receptor supersensitivity.