Behavioral differences in a rotenone-induced hemiparkinsonian rat model developed following intranigral or median forebrain bundle infusion.
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.
Sindhu
Kizhakke M
KM
Division of Clinical and Experimental Neuroscience, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India.
Saravanan
Karuppagounder S
KS
Mohanakumar
Kochupurackal P
KP
D018663:Adrenergic Agents / Q000008:administration & dosage; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005106:Exploratory Behavior / Q000187:drug effects; D007839:Functional Laterality / Q000187:drug effects; D008474:Medial Forebrain Bundle / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D016627:Oxidopamine / Q000008:administration & dosage; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011187:Posture; D051381:Rats; D045442:Rotarod Performance Test; D012402:Rotenone / Q000008:administration & dosage*; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
D018663:Adrenergic Agents; D004791:Enzyme Inhibitors; D012402:Rotenone; D016627:Oxidopamine; D000661:Amphetamine; D042967:Electron Transport Complex I; D004298:Dopamine