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Motor stereotypies are abnormally repetitive behaviors that can develop with excessive dopaminergic stimulation and are features of some neurologic disorders. To investigate the mechanisms required for the induction of stereotypy, we examined the responses of dopamine-deficient (DD) mice to increasing doses of the dopamine precursor l -DOPA. DD mice lack the ability to synthesize dopamine (DA) specifically in dopaminergic neurons yet exhibit robust hyperlocomotion relative to wild-type (WT) mice when treated with l -DOPA, which restores striatal DA tissue content to ≈10% of WT levels. To further elevate brain DA content in DD mice, we administered the peripheral l -amino acid decarboxylase inhibitor carbidopa along with l -DOPA (C/ l -DOPA). When striatal DA levels reached >50% of WT levels, a transition from hyperlocomotion to intense, focused stereotypy was observed that was correlated with an induction of c-fos mRNA in the ventrolateral and central striatum as well as the somatosensory cortex. WT mice were unaffected by C/ l -DOPA treatments. A D1, but not a D2, receptor antagonist attenuated both the C/ l -DOPA-induced stereotypy and the c-fos induction. Consistent with these results, stereotypy could be induced in DD mice by a D1, but not by a D2, receptor agonist, with neither agonist inducing stereotypy in WT mice. Intrastriatal injection of a D1 receptor antagonist ameliorated the stereotypy and c-fos induction by C/ l -DOPA. These results indicate that activation of D1 receptors on a specific population of striatal neurons is required for the induction of stereotypy in DD mice.

Mice that cannot make dopamine (DA), a condition caused by the selective inactivation of tyrosine hydroxylase in dopaminergic neurons, are born normal but gradually become hypoactive and hypophagic, and die at 3 weeks of age. We characterized the feeding and locomotor responses of these DA-deficient (DA−/−) mice to 3,4-dihyroxy- l -phenylalanine ( l -DOPA) to investigate the relationship between brain DA levels and these complex behaviors. Daily administration of l -DOPA to DA−/− mice stimulated locomotor activity that lasted 6 to 9 hr; during that time the mice consumed most of their daily food and water. The minimal dose of l -DOPA that was sufficient to elicit normal feeding behavior in the DA−/− mice also restored their striatal DA to 9.1% of that in the wild-type (WT) mice at 3 hr; then DA content declined to l -DOPA induced locomotor activity that exceeded that of treated WT mice by 5- to 7-fold, suggesting that DA−/− mice are supersensitive to DA. Unexpectedly, DA−/− mice manifested a second wave of activity 24 to 48 hr after l -DOPA treatment that was equivalent in magnitude to that of WT mice and independent of DA receptor activation. The DA−/− mice approached, sniffed, and chewed food during this second period of activity, but they ate