BLOCKADE OF PHENCYCLIDINE-INDUCED HYPERLOCOMOTION BY CLOZAPINE AND MDL-100,907 IN RATS REFLECTS ANTAGONISM OF 5-HT2A RECEPTORS

Whereas haloperidol more potently blocked the locomotion elicited by amphetamine (2.5 mg/kg i.p.) than that elicited by phencyclidine (PCP) (20.0 mg/kg s.c.), with inhibitory dose(50)s of 0.04 and 0.09 mg/kg s.c., respectively, clozapine more potently blocked the effect of PCP (0.04) than of amphetamine (8.8). Similarly, risperidone more potently blocked PCP (0.002) than amphetamine (0.2). In analogy to haloperidol, the selective dopamine D-2 receptor antagonist, raclopride, antagonised amphetamine (0.16) more potently than PCP (0.8) whereas the selective 5-HT2A receptor antagonist, [R(+)-alpha-(2,3-dimethoxyphenyl)-1 -[2-(4-fluorophenylethyl)]-4-piperidine-methanol] (MDL 100,907), only antagonised PCP (0.001) as compared to amphetamine (> 10.0). The potency for inhibition of PCP correlated more highly to affinity at 5-HT2A (r = 0.97, P < 0.01) than dopamine D-2 (0.57, P > 0.05) sites, while the potency for blockade of amphetamine correlated more highly with affinity at dopamine D-2 (0.94, P < 0.01) than at 5-HT2A sites (0.37, P > 0.05). In conclusion, in contrast to amphetamine, induction of locomotion by PCP is dependent upon functional 5-HT2A receptors, antagonism of which by 'atypical' antipsychotics underlies their ability to inhibit PCP-induced locomotion.