RISPERIDONE PREVENTS THE DEVELOPMENT OF SUPERSENSITIVITY, BUT NOT TOLERANCE, TO PHENCYCLIDINE IN RATS TREATED WITH SUBACUTE PHENCYCLIDINE

We investigated whether risperidone, a 5-HT2/dopamine-D-2 receptor ant agonist, inhibits the development of tolerance and supersensitivity to PCP and whether subacute administration of PCP with risperidone affec ts the [H-3]MK-801 binding in rat brain, in comparison with dopamine-D -2 receptor antagonist haloperidol and 5-HT2 receptor antagonist ritan serin. In rats treated with PCP (10 mg/kg, i.p.) for 14 days, PCP (10 mg/kg, i.p.)-induced hyperlocomotion, rearing and sniffing were potent iated (supersensitivity), and head-weaving, head-twitch, backpedalling and turning were diminished (tolerance). The development of supersens itivity to PCP was blocked by oral co-administration of risperidone (2 .4 mg/kg, p.o.) and haloperidol (1.0 mg/kg, p.o.) for 14 days, but not ritanserin (10 mg/kg, p.o.) and risperidone (0.8 mg/kg, p.o.), while no drugs prevented the development of tolerance to PCP. Both risperido ne (2.4 mg/kg, p.o.) and haloperidol(1.0 mg/kg, p.o.) also inhibited t he cross-supersensitivity to methamphetamine (MAP; 2.5 mg/kg, i.p.)-in duced rearing in rats treated with PCP for 14 days. The profiles of [H -3]MK-801 binding in discrete brain areas did not change after subacut e administration of PCP alone or in combination with risperidone, halo peridol or ritanserin for 14 days. Therefore, it is suggested that sub acute administration of PCP may cause functional changes in the dopami nergic neuronal transmission under conditions where the binding of [H- 3]MK-801 in discrete brain areas is unchanged, and that co-administrat ion of risperidone may block these PCP-induced changes in neuronal fun ction.