In vivo brain microdialysis studies on the striatal dopamine and serotonin release in zitter mutant rats.

In the present study, using in vivo brain microdialysis, we investigated the basal extracellular dopamine (DA) and serotonin (5-HT) release in the caudal striatum (cSTR) of young (4-6 months old) and aged (10-12 months old) zitter mutant rats. The basal extracellular levels of DA release in both young and aged zitter rats were significantly lower than that of age-matched Sprague-Dawley (SD) rats, whereas only aged zitter rats showed a significant difference in the basal 5-HT release. Dopaminergic neurons were more vulnerable than serotonergic neurons in the cSTR of zitter mutant rats during aging. Perfusion of 60 mM potassium (K+) enhanced the extracellular levels of cSTR DA in the young zitter rats and the extracellular levels of both DA and 5-HT in the cSTR of the aged zitter rats. The firing rate of K+-stimulated monoamine release in the cSTR was significantly higher in the zitter rats than in the age-matched SD rats. These findings suggest that there are innate quantitative differences in the releasable pool and the availability of monoamines in the cSTR of zitter mutant rats.

Progressive dopaminergic neurodegeneration of substantia nigra in the zitter mutant rat.

Zitter mutant rats exhibit abnormal metabolism of superoxide species and demonstrate progressive degeneration of dopamine (DA) neurons in the substantia nigra (SN). Furthermore, long-term intake of vitamin E, an effective free radical scavenger, prevents the loss of DA neurons caused by free radicals. However, it is unclear how this degeneration progresses. In this study, we ultrastructurally examined cell death in the zitter mutant rat SN. Conventional electron-microscopic examination revealed two different types of neurons in the SN pars compacta. In zitter mutant rats, although the first type (clear neurons) exhibited no obvious ultrastructural changes with aging, the second type (dark neurons) demonstrated age-related damage from 2 months. Immunoelectron-microscopic analysis clarified that the second-type neurons were dopaminergic neurons. In the dopaminergic neuronal somata, many lipofuscin granules and abnormal endoplasmic reticula were observed from 2 months of age, and these dopaminergic neurons showed progressive degeneration with age. Moreover, in zitter mutant rats, abnormally enlarged myelinated axons with dense bodies and splitting myelin with dense material were observed in the SN at 2, 4, and 12 months, and oligodendrocytes with numerous lipofuscin, multivesicular bodies, multilamellar bodies, and dense bodies were frequently observed at 4 and 12 months. These findings clarified that dopaminergic neurons in zitter mutant rats had degenerated with age, and that myelinated axons also exhibited age-related injury. Moreover, ubiquitin-immunohistochemical analysis indicated that the accumulation of products of the endosomal-lysosomal system may be involved in this degeneration.