Rats with unilateral median forebrain bundle, but not striatal or nigral, lesions by the neurotoxins MPP+ or rotenone display differential sensitivity to amphetamine and apomorphine.
ABSTRACT Rotenone and 1-methyl-4-phenyl pyridinium (MPP+) are two mitochondrial neurotoxins known to produce Parkinson's disease (PD) in experimental animals. In the present study, we compared drug-induced rotational asymmetry in rats lesioned using these neurotoxins at three distinct basal ganglia sites, the striatum, substantia nigra pars compacta (SNpc) and median forebrain bundle (MFB). The levels of dopamine (DA) in the ipsilateral striata of these hemiparkinsonian animals were assayed employing an HPLC-electrochemical procedure 2 days after the final rotational study. Rats infused with rotenone or MPP+ into the SNpc, but not into the striatum or MFB, exhibited contralateral rotations immediately after recovery from anesthesia. Irrespective of the lesion site or the toxin used, all the animals exhibited ipsilateral rotations when challenged with D-amphetamine. Apomorphine administration caused contralateral circling behavior in MFB-lesioned animals, but ipsilateral rotations in rats that received rotenone or MPP+ in the striatum or SNpc. Stereotaxic administration of rotenone into the MFB, SNpc or striatum caused a significant loss of DA in the ipsilateral striatum to varying degrees (96%, 62% and 30%, respectively, as compared to the contralateral side). However, unilateral MPP+ administration into the MFB, SNpc or striatum caused respectively about 98%, 74% and 59% loss of striatal DA. Behavioural observations and the neurochemical results indicate that, among the three anatomically distinct loci-lesioned, MFB-lesioned animals mimicked behavioral aberrations similar to nigral lesions caused by 6-hydroxydopamine, a classical parkinsonian neurotoxin. Moreover, the results point out that while both d-amphetamine and apomorphine-induced rotations could be considered as valuable behavioral indices to test novel drugs against PD, yet apomorphine-induced contralateral bias proves to be a more reliable indicator of specific destruction in the nigrostriatal pathway and development of post-synaptic DA receptor supersensitivity.
Article: Hemiparkinsonian rats rotate toward the side with the weaker dopaminergic neurotransmission.[show abstract] [hide abstract]
ABSTRACT: Rats with unilateral lesion of the substantia nigra pars compacta (SNpc) have been used as a model of Parkinson's disease. Depending on the lesion protocol and on the drug challenge, these rats rotate in opposite directions. The aim of the present study was to propose a model to explain how critical factors determine the direction of these turns. Unilateral lesion of the SNpc was induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Separate analysis showed that neither the type of neurotoxin nor the site of lesion along the nigrostriatal pathway was able to predict the direction of the turns these rats made after they were challenged with apomorphine. However, the combination of these two factors determined the magnitude of the lesion estimated by tyrosine-hydroxylase immunohistochemistry and HPLC-ED measurement of striatal dopamine. Very small lesions did not cause turns, medium-size lesions caused ipsiversive turns, and large lesions caused contraversive turns. Large-size SNpc lesions resulted in an increased binding of [(3)H]raclopride to D2 receptors, while medium-size lesions reduced the binding of [(3)H]SCH-23390 D1 receptors in the ipsilateral striatum. These results are coherent with the model proposing that after challenged with a dopamine receptor agonist, unilaterally SNpc-lesioned rats rotate toward the side with the weaker activation of dopamine receptors. This activation is weaker on the lesioned side in animals with small SNpc lesions due to the loss of dopamine, but stronger in animals with large lesions due to dopamine receptor supersensitivity.Behavioural Brain Research 07/2008; 189(2):364-72. · 3.42 Impact Factor