EFFECTS OF SEROTONERGIC AGENTS ON THE UP-REGULATION OF DOPAMINE D-2 RECEPTORS INDUCED BY HALOPERIDOL IN RAT STRIATUM

We examined the modulatory effect of serotonergic activities on halope ridol-induced up-regulation of dopamine D-2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) in creased the number of dopamine D-2 receptors, while no increase was ob served with the atypical antipsychotic drugs clozapine (10 mg/kg) and ahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate (ORG 5222; 0.25 mg/kg). Chronic treatment with 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a nonselective serotonin (5-hydroxytryptamine, 5-HT) recept or agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulat ion of dopamine D-2 receptors, while that with (+/-)-8-hydroxy-2-(di-n -propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/k g) had no influence on the dopamine D-2 receptor up-regulation. Coadmi nistration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, w ith a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg) attenuated the dopamine D-2 receptor up-regulat ion. Drug occupation of 5-HT2A and dopamine D-2 receptors in vivo exam ined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 6 9.8% and 45.1%, respectively, after the acute administration of halope ridol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT2A receptors are highly occupied compared with dopamine D-2 receptors, w as similar to that of clozapine or ORG 5222. These results suggest tha t potent 5-HT2A receptor antagonism versus weak dopamine D-2 receptor blockade may be involved in the absence of up-regulation of dopamine D -2 receptors after chronic treatment with clozapine or ORG 5222.