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One of the crucial breakthroughs in research on parkinsonism was the observation of circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model remains one of the basic animal models of Parkinson's disease. We report here the first mutant rat strain with abnormal circling behaviour and several other features reminiscent of the Ungerstedt Parkinson model. The neurological disorder in the novel mutant rat strain is determined monogenetically by a recessive autosomal gene termed circling (ci). Mutant rats of both genders exhibit an intense asymmetric circling in an open-field or rotometer, which is enhanced by treatment with amphetamine. Neurochemical determinations show that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. Furthermore, in a forelimb-reaching test for assessing the skilled motor capacities of rats, ci rats show a marked deficit on the side contralateral to the preferred direction of turning, which is analogous to motor deficits previously described for rats subjected to unilateral 6-hydroxydopamine lesions. The new mutant rat strain thus exhibits remarkable similarities to the Ungerstedt model and could be used to study the endogenous processes, particularly the genetic components, that might eventually lead to progressive motor dysfunctions.

Abnormal circling behavior in rodents is usually attributed to vestibular dysfunction. In rats, all circling mutants described previously have inner ear defects resulting in auditory and vestibular dysfunctions. Here, we describe a new mutant rat with abnormal spontaneous circling behavior but normal auditory and vestibular functions. The new circling mutant rat was discovered in progeny of an apparently normal black-hooded (BH) rat inbred line [BH.7A(LEW)/Won] and was termed ci3, because we recently found two other mutant circling rats (ci1 and ci2) in a Lewis (LEW) inbred rat strain. The ci3 mutant is characterized by circling behavior and locomotor hyperactivity, which occur in phases or bursts either spontaneously or in response to stress, e.g., when rats are transferred to a new environment. Video monitoring of undisturbed rats in their home cage during the light and dark periods showed that circling behavior is much more intense during the dark period, i.e., during the active phase of the animals. Most ci3 rats show a lateral preference in their rotational behavior, i.e., they either rotate to the left or to the right. Brainstem auditory evoked potential testing and different tests of vestibular function did not disclose any auditory or marked vestibular defects in ci3 rats. Furthermore, no morphological abnormalities were seen during histological examination of the cochlear and vestibular nuclei in the brainstem. Neurochemical determination of dopamine and dopamine metabolite levels in striatum, nucleus accumbens and substantia nigra showed that ci3 rats have a significant asymmetry in striatal dopamine in that dopamine levels were significantly lower in the hemisphere contralateral to the preferred direction of turning. Consistent with this finding, immunohistological examination of dopaminergic neurons in substantia nigra and ventral tegmental area yielded a significant laterality in the medial part of substantia nigra pars compacta with a lower density of tyrosine hydroxylase-positive neurons in the contralateral hemisphere of mutant circling rats, while no laterality was seen in unaffected rats of the background strain [BH.7A(LEW)/Won].Thus, the novel mutant ci3 rat exhibits several features which clearly differ from previously described circling rat or mouse mutants. The behavioral phenotype occurs in the absence of auditory or obvious vestibular defects and is most likely a consequence of lateralized abnormalities found in the nigrostriatal circuit. Apart from the use of ci3 rats for studying the functional lateralization of brain functions, the ci3 mutant may serve as a new model for movement disorders with abnormal lateralization.