The effects of clozapine on behavioural responses to the selective 'D1-like' dopamine receptor agonist, A 68930, and to the selective 'D2-like' agonist, RU 24213.
1. The influence of the atypical antipsychotic clozapine on D1 dopamine receptor-mediated function was examined in terms of its effects on behavioural responses to the new isochroman selective D1 agonist, A 68930, and to the selective D2 agonist, RU 24213. 2. In rat striatal membrane preparations, radioligand binding studies with [3H]-SCH 23390 and [3H]-spiperone confirmed clozapine to show weak and non-selective affinity for both D1 and D2 receptors. 3. Using a rapid time-sampling behavioural check list technique, clozapine (4.0-36.0 mg kg-1) exerted only modest antagonism of RU 24213 (15.0 mg kg-1)-induced sniffing and locomotion, and weakly released some episodes of myoclonic jerking; such antagonism with release of jerking has been shown previously to occur only during concurrent stimulation of D2 receptors and attenuation of D1 function. 4. Over the same dose-range, clozapine completely blocked A 68930 (0.25 mg kg-1)-induced intense grooming but failed to influence the vacuous chewing response; this profile was similar to that demonstrated previously for selective D1 antagonists. 5. On the basis of complete blockade of typical D1 agonist-induced grooming and weak release of atypical jerking to D2 agonism in the face of modest reduction in typical D2-stimulated behaviours, clozapine appears to exert some preferential but not selective attenuation of D1 receptor-mediated function. Clozapine may attenuate activity through a classical D1 receptor at a level beyond the recognition site, for which it has little affinity, or by way of new, putative 'D1-like' site(s) that subserve distinct elements of dopaminergic behaviour.
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
S A
SA
Daly
J L
JL
Waddington
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*
D002839:Chromans; D018491:Dopamine Agonists; D010627:Phenethylamines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C016868:N-n-propyl-N-phenylethyl-4(3-hydroxyphenyl)ethylamine hydrochloride; C065380:A 68930; D003024:Clozapine