Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation

Motor stereotypies are abnormally repetitive behaviors that can develop wit h excessive dopaminergic stimulation and are features of some neurologic di sorders. To investigate the mechanisms required for the induction of stereo typy, we examined the responses of dopamine-deficient (DD) mice to increasi ng doses of the dopamine precursor L-DOPA. DD mice lack the ability to synt hesize dopamine (DA) specifically in dopaminergic neurons yet exhibit robus t hyperlocomotion relative to wild-type (WT) mice when treated with L-DOPA, which restores striatal DA tissue content to approximate to 10% of WT leve ls. To further elevate brain DA content in DID mice, we administered the pe ripheral 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 t hese results, stereotypy could be induced in DD mice by a DI, but not by a D2, receptor agonist, with neither agonist inducing stereotypy in WT mice. Intrastriatal injection of a D1 receptor antagonist ameliorated the stereot ypy 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 f or the induction of stereotypy in DD mice.