Enhancement of latent inhibition by two 5-HT2A receptor antagonists only when given at both pre-exposure and conditioning.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.).


CONCLUSIONS
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.
McDonald
L M
LM
Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. Louise_McDonald@Merck.com
Moran
P M
PM
Vythelingum
G N
GN
Joseph
M H
MH
Stephenson
J D
JD
Gray
J A
JA
D006916:5-Hydroxytryptophan / Q000009:adverse effects; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000009:adverse effects; D000375:Aging; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001522:Behavior, Animal; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000494:pharmacology*; D007266:Inhibition, Psychological; D008297:Male; D010622:Phencyclidine / Q000009:adverse effects; D010636:Phenols / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000009:adverse effects; D013239:Stereotyped Behavior / Q000187:drug effects
D000697:Central Nervous System Stimulants; D005464:Fluorobenzenes; D010636:Phenols; D011804:Quinolines; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; C076033:SR 46349B; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C054363:2-((2-(dimethylamino)ethyl)thio)-3-phenylquinoline; D006916:5-Hydroxytryptophan; D000661:Amphetamine; D010622:Phencyclidine