Differential response of cortical-limbic neuropotentiated compulsive mice to dopamine D1 and D2 receptor antagonists

We previously created transgenic mice in which dopamine D-1 receptor-expressing (D1 +) neurons in regional subsets of the cortex and amygdala express a neuropotentiating cholera toxin (CT) transgene. These 'D1CT' mice engage in complex biting, locomotor and behavioral perseverance-repetition abnormalities that resemble symptoms of human compulsive disorders associated with cortical-limbic hyperactivity. Because excessive cortical-limbic stimulation of striatal motor pathways may play a critical role in causing compulsive disorders, we examined the responsiveness of D1CT mice to dopamine D-1 and D-2 receptor antagonists. D1CT mice were found to be largely resistant to the cataleptic action of the D-1 receptor antagonist SCH23390. The abnormal repetitive leaping of D1CT mice was similarly unaffected by SCH23390. In contrast, the DICT mice displayed supersensitivity to cataleptic induction by the D-2 receptor antagonist sulpiride. These data are consistent with the hypothesis that complex compulsions are mediated by chronic excessive corticostriatal (and/or amygdalostriatal) glutamatergic stimulation of the striatal direct and indirect motor pathways. (C) 1999 Elsevier Science B.V. All rights reserved.