ICI-169369

Clozapine-like atypical antipsychotic drugs, such as olanzapine, risperidone and sertindole, bind most strongly to 5-HT(2A) receptors, which may contribute to their antipsychotic effects. Antipsychotic drugs, such as clozapine and haloperidol, have been found to enhance latent inhibition (LI) in humans and rats. LI is a process of learning to ignore irrelevant stimuli that is disrupted in acute, positive-symptom schizophrenia, and can be modelled in animals.

The aim of this study was to determine the effects of two selective 5-HT(2A) receptor antagonists, SR 46,349B and ICI 169,369, on LI, as a test of their antipsychotic potential.

Doses of the 5-HT(2A) receptor antagonists that were sufficient for receptor blockade were determined in 5-HT behavioural syndrome tests. SR 46,349B and ICI 169,369 were then tested for enhancement of LI and reversal of amphetamine-induced attenuation of LI in a conditioned suppression paradigm.

SR 46,349B (0.6-2.4 mg kg(-1) i.p.) and ICI 169,369 (10-40 mg kg(-1) i.p.) antagonised 5-hydroxytryptophan (5-HTP)-induced head twitches and wet dog shakes, which are mediated by 5-HT(2A) receptors, but had no effect on mCPP-induced hypolocomotion, which is mediated by 5-HT(2C) receptors. Neither SR 46,349B (1.2 mg kg(-1) i.p.) nor ICI 169,369 (40 mg kg(-1) i.p) affected 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT)-induced forepaw treading, suggesting that they were not in vivo 5-HT(1A) receptor antagonists. SR 46,349B (2.4 mg kg(-1) i.p.) and ICI 169,369 (40 mg kg(-1) i.p.) enhanced LI when given at both the pre-exposure and conditioning stages of the paradigm, but not when given at either pre-exposure or conditioning only. Both drugs also reversed the disruption of LI induced by D-amphetamine (1 mg kg(-1) i.p.).

The profile of SR 46,349B and ICI 169,369 in LI differs from that of clozapine and haloperidol in LI, which both enhance LI when given only at the conditioning stage of the paradigm.

Selective 5-hydroxytryptamine (5-HT) receptor antagonists were employed to further characterize the receptor subtypes mediating the contractile actions of 5-HT on the isolated uterine preparations of the rat. Increasing concentrations (10(-8)-10(-6) M) of the 5-HT receptor antagonist methysergide produced rightward shifts of the concentration-response curves of the 5-HT-induced contractions (pA2=8.05, slope of A-S plot=1.12 n=7) ketanserin a 5-HT2A receptor antagonist (10(-8)-10(-6) M) competitively antagonized the actions of 5-HT on the preparation (pA2=8.81; slope=1.04; n=7). Both LY53857 (10(-8)-10(-6) M) and ICI169369 (10(-8)-10(-6) M) which are known 5-HT2 receptor blockers also produced concentration-dependent shifts of the curves LY53857 yielded a pA2 of 8.9 (slope=0.82; n=7) while the pA2 for ICI169369 on the preparation was 7.9 (slope=1.29; n=7). ICS205930 a potent 5-HT3 blocker (10(-12)-10(-9) M) also produced concentration-dependent shifts of the curves (pA2=11.3; slope=0.94; n=7). The presence of 5-HT1 receptors could not be established. However both 5-HT2 and 5-HT3 receptors seem to be present on the rat uterine preparation.