title: Disruption of latent inhibition in the rat by the 5-HT2 agonist DOI: effects of MDL 100,907, clozapine, risperidone and haloperidol.
abstract: Latent inhibition (LI), a measure of the ability to learn to ignore irrelevant stimuli, is disrupted in acute schizophrenics and in rats treated with amphetamine; antipsychotics prevent amphetamine disruption of LI in rats. The 5-HT2A/C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has hallucinogenic properties in humans, and evidence suggests that 5-HT2 antagonism is an important component of atypical antipsychotic activity. Therefore, the ability of DOI to disrupt LI in rats was tested, and the ability of clinically-used and putative antipsychotics to reverse DOI disruption of LI was assessed. The method consisted of four phases. After habituation to the apparatus, thirsty rats underwent preexposure to a tone stimulus 24 h prior to two tone-shock conditioning trials. LI was demonstrated at testing (an additional 24 h later) by reduced lick suppression during tone presentation. When administered at the preexposure phase only, DOI disrupted LI. However, when administered at both preexposure and conditioning phases, DOI did not disrupt LI except at the highest dose, where lick suppression itself was also disrupted. Therefore, disruptive effects of DOI on LI are not easily dissociated from state-dependent learning effects. Additional experiments demonstrated that haloperidol, clozapine, risperidone, and the selective 5-HT2A antagonist MDL 100,907 prevented the disruptive effects of DOI on LI when administered at preexposure only. These results agree with findings that these compounds can also prevent other behavioral effects of DOI. Further experiments will be required to explore the possible involvement of state-dependent learning effects in the present results. However, if the disruptive effects of DOI on LI are due to an influence on attentional processes rather than state-dependent learning, this procedure may have potential as a method for detection of antipsychotic activity.
authors.affiliation: Hoechst Marion Roussel, Inc., CNS Research, Bridgewater, NJ 08807, USA. hitchcock@lsgbw.hcc.com
authors.forename: J M
authors.initials: JM
authors.lastname: Hitchcock
authors.forename: S
authors.initials: S
authors.lastname: Lister
authors.forename: T R
authors.initials: TR
authors.lastname: Fischer
authors.forename: J G
authors.initials: JG
authors.lastname: Wettstein
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012054:Reinforcement, Psychology; D018967:Risperidone / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D000662:Amphetamines; D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D010880:Piperidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C079049:volinanserin; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine