Pigeons were trained to discriminate i.m. injections of the atypical antipsychotic clozapine (1.0 mg/kg) from saline in a two-key operant procedure. In substitution tests, compounds that shared antagonistic action at 5-hydroxytryptamine (5-HT)(1C) and 5-HT2 receptors produced discriminative stimulus effects similar to clozapine: cyproheptadine, metergoline, mianserin, pizotifen and fluperlapine, 5-HT antagonists selective for 5-HT2 vs. 5-HT(1C) receptors (e.g., ketanserin, pirenperone, risperidone and methiothepin) failed to produce substantial clozapine- appropriate responding. Other serotonergic compounds failed to produce substantial clozapine-appropriate responding: the 5-HT3 antagonist, ondansetron; the 5-HT(1A) agonists, (±)-8-hydroxy-2-(di-n- propylamino)tetralin and BMY 14802; the 5-HT(1A/1B) agonist, RU24969; the 5- HT(1A) partial agonist, NAN190; the 5-HT(1C/2) antagonist, mesulergine; the 5-HT1 agonist, I-5-hydroxytryptophane; and the 5-HT(1C/2) agonist, quipazine. Other reference compounds such as the typical antipsychotics, chlorpromazine and thioridazine; the selective dopamine D-2 antagonists, droperidol and sulpiride; the dopamine D-1 antagonist, SCH 23390; the antimuscarinics, atropine and scopolamine; the antihistamines, pyrilamine and diphenhydramine; the alpha-1 antagonist, prazosin; and the anti-depressants, imipramine and chloromipramine also failed to produce clozapine-appropriate responding. Promethazine, cinanserin and amitriptyline produced only partial generalization to the clozapine cue. The results suggest that blockade of both 5-HT2 and/or 5-HT(1C) receptors is important in the pharmacological mediation of the discriminative stimulus effects of clozapine. Blockade of 5- HT2 receptors appears not to be sufficient to produce clozapine-like discriminative stimulus effects. The precise role of 5-HT(1C) receptors in the clozapine discriminative stimulus is unclear due to the lack of compounds selective for this receptor. This experiment has provided further evidence in support of an antiserotonergic effect of clozapine and is the first to report a 5-HT(1C) antagonist effect in vivo which may be an important component of clozapine's unique pharmacological profile as an atypical antipsychotic.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1992|
ASJC Scopus subject areas
- Molecular Medicine