Receptor fingerprinting the circling ci2 rat mutant: insights into brain asymmetry and motor control.

Circling behaviour of the ci2 rat mutant, a model for hyperkinetic movement disorders, is associated with an abnormal asymmetry in striatal dopaminergic activity. Since it is more likely that imbalances in several neurotransmitter systems result in the cascade of neurochemical disturbances underlying disorders involving motor dysfunctions, we measured the densities of 12 neurotransmitter receptors in the basal ganglia and vestibular nuclei of adult circling mutants (ci2/ci2), non-circling littermates (ci2/+) and controls from the background strain (LEW/Ztm). In controls, the left caudate putamen (CPu) contains lower kainate and the left globus pallidus higher AMPA densities than their right counterparts. The medial vestibular nucleus of mutants ipsilateral to the preferred direction of rotation contained higher M2 densities than the contralateral one. ci2/+ animals presented no interhemispheric differences, did not differ behaviourally from controls, but contained lower GABAA densities in the CPu, nucleus accumbens (Acb) and reticular (Rt), ventromedial (VM) and ventral posterolateral (VPL) thalamic nuclei. Mutants contained lower GABAA (CPu, Acb, Rt, VPL) but higher nicotinic (Rt, VM) densities than controls and higher GABAA (CPu, VM) densities than ci2/+ rats. Hyperactivity level of mutants was positively correlated with the adenosine A2A receptor densities in the ipsilateral Acb, but negatively correlated with those of the ipsilateral thalamus. Concluding, ci2/ci2 mutants show alterations in GABAA, cholinergic and A2A receptor densities. Our data add to the hypothesis that motor disorders such as hyperkinesias cannot be explained solely by absolute functional increases or decreases in the dopaminergic system, but are due to imbalances in several neurotransmitter systems.

Auditory and vestibular defects and behavioral alterations after neonatal administration of streptomycin to Lewis rats: Similarities and differences to the circling (ci2/ci2) Lewis rat mutant.

The clinical usefulness of aminoglycoside antibiotics is limited by their ototoxicity. In rodents, damage to the inner ear is often associated with rotational behavior and locomotor hyperactivity reminiscent of such behaviors resulting from an imbalance of forebrain dopamine systems. Based on previous observations in the circling (ci2/ci2) Lewis (LEW) rat mutant, a spontaneous mutation leading to hair cell loss, deafness, impairment of vestibular functions, lateralized circling, hyperactivity and alterations in the nigrostriatal dopamine system, we have recently hypothesized that vestibular defects during postnatal development, independent of whether induced or inherited, lead to secondary changes in the dopaminergic system within the basal ganglia, which would be a likely explanation for the typical behavioral phenotype seen in such models. In the present study, we directly compared the phenotype induced by streptomycin in LEW rats with that of the ci2 LEW rat mutant. For this purpose, we treated neonatal LEW rats over 3 weeks by streptomycin, which induced bilateral degeneration of cochlear and vestibular hair cells. Following this treatment period, the behavioral syndrome of the streptomycin-treated animals, including the lateralized rotational behavior, was almost indistinguishable from that of ci2 mutant rats. However, in contrast to the ci2 mutant rat, all alterations, except the hearing loss, were only transient, disappearing between 7 and 24 weeks following treatment. In conclusion, in line with our hypothesis, vestibular defects induced in normal LEW rats led to the same phenotypic behavior as the inherited vestibular defect of ci2 mutant rats. However, with increasing time for recovery, adaptation to the vestibular impairment developed in streptomycin-treated rats, while all deficits persisted in the mutant animals. At least in part, the transient nature of the abnormal behaviors resulting from treatment with streptomycin could be explained by adaptation to the vestibular impairment by the use of visual cues, which is not possible in ci2 rats because of progressive retinal degeneration in these mutants. Although further experiments are needed to prove this hypothesis, the present study shows that direct comparisons between these two models serve to understand the mechanisms underlying the complex behavioral phenotype in rodents with vestibular defects and how these defects are compensated.

Marked differences in response to dopamine receptor antagonism in two rat mutants, ci2 and ci3, with lateralized rotational behavior.

We have recently described two rat mutants, ci2 and ci3, in which abnormal lateralized rotational behavior and locomotor hyperactivity occur either spontaneously or in response to external stimuli, such as new environment. While cochlear and vestibular defects are found in ci2 rats, ci3 rats do not exhibit any inner ear abnormalities. Both mutants show abnormal lateralities in striatal dopamine and in the density of dopaminergic neurons in substantia nigra or ventral tegmental area, which may be involved in the behavioral phenotype of these rats. In line with this hypothesis, the circling behavior of the ci2 and ci3 mutants is intensified by amphetamine. In the present study, we evaluated the effects of dopamine receptor blockade on the abnormal behaviors of ci2 and ci3 rats. Haloperidol blocked the hyperactivity in both mutants, but this was most likely due to the known inhibitory effect on locomotion by this drug. When animals were observed during the light phase, the abnormal rotational behavior of the mutants was not significantly affected by haloperidol, whereas the dopamine D2 receptor-preferring antagonist raclopride significantly reduced rotations in ci2 rats. When the behavior of the ci3 rats was video-monitored during the dark phase, circling was significantly inhibited by haloperidol. The most striking difference between the two mutants was that ci2 rats were less susceptible than the unaffected littermates to the cataleptogenic effects of haloperidol and raclopride, whereas no such difference was observed in ci3 rats. These data demonstrate that, although there are several similarities between the ci2 and ci3 rat mutants, their cataleptogenic response to dopamine receptor blockade strikingly differs. The comparative evaluation of these two rat mutants may help to increase our understanding of the relationship between developmental anomalies of cerebral asymmetry and brain disorders.