Differential response of cortical–limbic neuropotentiated compulsive mice to dopamine D 1 and D 2 receptor antagonists

Abstract

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 D1CT 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.