Dopamine Deficiency in the Weaver Mutant Mouse1

The dopamine system in weaver mutant mice (BGCBA-AwmJ/A background) was studied. Dopamine was 27% lower in the olfactory tubercle, 77% lower in the frontal cortex, and 75% lower in the striatum of 6-month-old weaver mice compared to control mice of the same age. Norepinephrine and serotonin were not lower in these brain areas. Tyrosine hydroxylase activity in the striatum was measured with a radiometric assay and was 70% lower in weaver mice. Examination of mice from 11 to 180 days of age revealed that the dopamine system failed to develop in weaver mice. Motor activity in individual animals was assessed using circular photocell activity cages with minimal illumination. Apomorphine and pergolide, direct dopamine agonists, increased activity more in weaver mice than in normal littermates. Amphetamine, which releases endogenous stores of dopamine, was less active in mutant mice. These findings provide suggestive evidence that postsynaptic dopamine receptors in weaver mutants might have become supersensitive as a result of lower levels of dopamine in motor areas of the brain. Anatomical evidence of dopamine system abnormalities was found in weaver mice by examination of serial sections cut from the midbrain of mutant and normal mice. The pars compacta of the substantia nigra in weaver mice appeared hypocellular when compared with the corresponding sections from controls. Fewer large neurons were seen in the affected animals. This study illustrates that weaver mice have specific deficiencies in the dopamine system. The weaver mouse might provide a way of examining the biochemical and behavioral effects of long term dopamine deficiency and a way to examine drugs to treat dopamine-deficient states in Go. The weaver mutant mouse (Sidman, 1968) is characterized behaviorally by ataxia and a fine tremor. Histologically, there is an atrophy of the cerebellum which is secondary to a failure of migration and to the degeneration of the cerebellar granule cells (Rakic and Sidman, 1973). However, there is evidence that the dopamine system also is affected in the weaver mutant. Lane et al. (1977) reported that the level of dopamine in the whole brain of adult weaver mice was 50% lower than in normal littermates. The present experiments were undertaken to better define the alterations in the dopamine system in weaver mice from a morphological, biochemical, and behaviorally pharmacological standpoint and, in this respect, to establish whether the weaver mouse could serve as a model of human disorders characterized by dopamine deficiency (e.g., Parkinson’s disease). ’ We would like to thank Mrs. Dorothy Meyer and Ms. Constance C. Alyea for their skillful assistance. This study was supported in part by National Institutes of Health Grant PHS-l-ROlNS14426 to B. G. ’ To whom correspondence should be addressed. Materials and Methods Weaver mutant mice (BGCBA-A”-“/A background) and heterozygous littermates were obtained from the Jackson Laboratories (Bar Harbor, ME) or raised from Jackson stock in our colony. Animals were housed in 15 x 20 cm plastic cages at 23 to 24°C and were given water and Purina Laboratory Chow ad libitum. Mice were weaned at 25 days of age and litters were kept together until used. Control and weaver mice were evaluated simultaneously in all assays or tests. However, due to the difficulty in obtaining sizable numbers of animals of specific ages on a given date, it was not possible to include all ages simultaneously in longitudinal experiments. A histological examination of the substantia nigra was made in weaver and control mice. Brain tissue was dissected from mice which had been decapitated. The brain stem, including the midbrain, was fixed in 10% formalin, while the remainder was used for neurochemical determinations in some cases. The brain stems from six weaver mice and six control mice were fixed in formalin, dehy-