Effects of serotonergic agents on the up-regulation of dopamine D 2 receptors induced by haloperidol in rat striatum

Abstract

We examined the modulatory effect of serotonergic activities on haloperidol-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) increased the number of dopamine D 2 receptors, while no increase was observed with the atypical antipsychotic drugs clozapine (10 mg/kg) and trans-5-chloro-2-methyl-2,3,3 a,12 b-tetrahydro-1 H-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) receptor 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-regulation of dopamine D 2 receptors, while that with (±)-8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), a 5-HT 1A receptor agonist (0.1 mg/kg) had no influence on the dopamine D 2 receptor up-regulation. Coadministration of ritanserin (1 mg/kg), a 5-HT 2A/2C receptor antagonist, with 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-regulation. Drug occupation of 5-HT 2A and dopamine D 2 receptors in vivo examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile, that 5-HT 2A receptors are highly occupied compared with dopamine D 2 receptors, was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT 2A 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.