A microdialysis study of striatal dopamine release in the circling rat, a genetic animal model with spontaneous lateralized rotational behavior

Abstract

The circling rat is an autosomal recessive mutant (homozygous ci2/ ci2) that displays lateralized circling behavior, locomotor hyperactivity, hyperexcitability, ataxia, and stereotypic head-movement. These abnormal behaviors are induced or intensified by stress. Heterozygous ( ci2/+) littermates display normal spontaneous behaviors. We have previously found that ci2 rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the rats turn away from the brain hemisphere with higher striatal dopaminergic activity. For further evaluation as to whether the spontaneous turning behavior of the mutant rats results from specific disturbances within the nigrostriatal circuitry, we used microdialysis in freely moving mutant rats and their unaffected littermates to measure extracellular levels of dopamine and its metabolites in the striatum of both hemispheres. Rats were habituated to the experimental procedures, so that mutant animals behaved as normal during a first phase of microdialysis (“rest phase”), which was followed by a “stress phase” with induction of lateralized circling by handling-stress. During rest, no significant imbalance in striatal dopamine release was observed in mutant rats, their unaffected littermates, and a second control group consisting of normal, unaffected rats from the same Lewis/Ztm strain. Stress induced a significant increase in dopamine release in the contralateral striatum of mutant rats of both genders, whereas no significant alterations in dopamine release were seen in either the left or right striatum of control groups. When amphetamine (100 or 500 μM) was added to the perfusion medium, the evoked dopamine release in the contralateral striatum of female mutant rats was significantly higher than that in the ipsilateral striatum, whereas no such asymmetry was observed in male mutants or unaffected female and male controls. The data further substantiate that mutant circling rats possess a genetically mediated dysfunction of the central dopaminergic system, but it remains to be determined whether neurochemical disturbances in other regions contribute to the behavioral phenotype of the ci2 rat. The continued study of this mutant may provide important new insights into the anatomical, neurochemical and molecular basis of hyperkinetic motor syndromes and other disorders related to dopaminergic dysfunction.