Immunohistochemical and neurochemical studies on nigral and striatal functions in the circling (ci) rat, a genetic animal model with spontaneous rotational behavior.

Asymmetrical spontaneous turning behavior or circling phenomena are often related to components of the dopaminergic system, particularly to an imbalance of nigrostriatal function. When a rotational preference is observed, it is typically in a direction away from the brain hemisphere with higher striatal dopaminergic transmission. We have recently described a rat mutant (ci) with spontaneous circling behavior and other signs of functional brain asymmetry. Neurochemical determinations showed that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. In the present study, we used immunohistochemical, neurochemical, and autoradiographic techniques to characterize the dopaminergic abnormalities of the ci rat mutant in more detail. Age-matched non-affected controls of the same strain were used for comparison. Immunohistochemical labeling of dopaminergic neurons and fibers in substantia nigra pars compacta, ventral tegmental area, and striatum did not indicate any significant neurodegeneration or asymmetry that could explain the lateralization in dopamine levels in striatum of ci rats. Neurochemical determinations substantiated that ci rats of both genders have a significant imbalance in striatal dopamine metabolism, but a similar significant lateralization was also seen in non-affected female controls. Comparison of dopamine, serotonin, noradrenaline and several monoamine metabolite levels in substantia nigra, striatum, nucleus accumbens and frontal cortex of ci rats and controls did not disclose any marked difference between affected and non-affected animals which was consistently found in both genders. Quantitative autoradiographic determination of binding densities of dopamine transporter and D1 and D2 receptors in several parts of the striatum and substantia nigra indicated that ci rats have a significantly higher binding density of dopamine transporter and receptors than controls. Taken together, ci mutant rats of both genders exhibit an asymmetry in striatal dopamine and metabolite levels and an enhanced dopamine transporter and receptor binding, but the link of these differences in dopaminergic parameters with the rotational behavior of the animals is not clear yet. The lack of any significant dopaminergic cell loss in the substantia nigra and the locomotor hyperactivity observed in the mutants clearly suggest that the ci rat is not suited as a model of Parkinsonism but rather constitutes a model of a hyperkinetic motor syndrome.