title: Clozapine reversal of the deficits in coordinated movement induced by D2 receptor blockade does not depend upon antagonism of alpha2 adrenoceptors.
abstract: Alpha2 adrenoceptor antagonists have been shown to reverse D2-antagonist-induced catalepsy leading to the hypothesis that the alpha2 antagonistic properties of clozapine underlie the compound's lack of extrapyramidal symptoms in the clinic. The potential for alpha2 antagonists to reverse the motor deficits produced by D2 antagonists (loxapine and haloperidol) was further investigated using a rotating rod (3.5 rpm) test in male Sprague-Dawley rats that requires coordinated movement to perform the task. The effects of loxapine (0.3 mg/kg, s.c.) were dose-dependently and statistically significantly reversed by the administration of clozapine (1,3, 10 mg/kg, i.p., n=10). Isoloxapine (1 mg/kg, i.p.), RX 821002 (2-methoxy-idazoxan; 5.6 mg/kg, i.p.) and yohimbine (5.6 mg/kg, i.p.) did not reverse the effects 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/kg, i.p.). On the other hand, scopolamine (0.03-0.3 mg/kg, i.p.) dose-dependently and statistically significantly antagonised the effects of both loxapine and haloperidol. These results indicate that the anticholinergic rather than the alpha2 antagonistic properties of clozapine may mediate the reversal of the motor deficit induced by D2 antagonism in a rotating rod test.
authors.affiliation: Nervous System Department, Novartis Pharma AG, Basel, Switzerland. kevin.mcallister@pharma.novartis.com
authors.forename: K H
authors.initials: KH
authors.lastname: McAllister
authors.forename: B
authors.initials: B
authors.lastname: Rey
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000188:drug therapy*; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008152:Loxapine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018727:Muscarinic Antagonists; D015016:Yohimbine; D012601:Scopolamine; C058525:2-methoxyidazoxan; D003024:Clozapine; D006220:Haloperidol; D008152:Loxapine; D019329:Idazoxan