Clozapine reversal of the deficits in coordinated movement induced by D-2 receptor blockade does not depend upon antagonism of alpha(2) adrenoceptors

alpha(2) Adrenoceptor antagonists have been shown to reverse D-2-antagonist -induced catalepsy leading to the hypothesis that the alpha(2) antagonistic properties of clozapine underlie the compound's lack of extrapyramidal sym ptoms in the clinic. The potential for alpha(2) antagonists to reverse the motor deficits produced by D-2 antagonists (loxapine and haloperidol) was f urther investigated using a rotating rod (3.5 rpm) test in male Sprague-Daw ley rats that requires coordinated movement to perform the task. The effects of loxapine (0.3 mg/kg, s.c.) were dose-dependently and statist ically significantly reversed by the administration of clozapine (1,3, 10 m g/kg, i.p., n=10). Isoloxapine (1 mg/kg, i.p.), RX 821002 (2-methoxy-idazox an; 5.6 mg/kg, i.p.) and yohimbine (5.6 mg/kg, i.p.) did not reverse the ef fects of loxapine. Furthermore, the motor deficits produced by haloperidol could not be reversed by RX 821002 (5.6 mg/kg, i.p.) or yohimbine (5.6 mg/k g, i.p.). On the other hand, scopolamine (0.03-0.3 mg/kg, if) dose-dependen tly and statistically significantly antagonised the effects of both loxapin e and haloperidol. These results indicate that the anticholinergic rather than the alpha(2) an tagonistic properties of clozapine may mediate the reversal of the motor de ficit induced by D-2 antagonism in a rotating rod test.