title: Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors.
abstract: The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus.
authors: Psychology Department, Northern Michigan University, Marquette, MI, USA. Electronic address: aprus@nmu.edu.
authors: Adam J
authors: AJ
authors: Prus
authors: Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
authors: Laura E
authors: LE
authors: Wise
authors: Lundbeck Research USA, Paramus, NJ, USA.
authors: Alan L
authors: AL
authors: Pehrson
authors: Lundbeck Research USA, Paramus, NJ, USA.
authors: Scott D
authors: SD
authors: Philibin
authors: Research and Development, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
authors: Benny
authors: B
authors: Bang-Andersen
authors: Sunred Pharm Consulting Aps, Solrød Strand, Denmark.
authors: Jørn
authors: J
authors: Arnt
authors: Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.
authors: Joseph H
authors: JH
authors: Porter
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D003024:Clozapine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D005464:Fluorobenzenes / Q000008:administration & dosage; D005793:Generalization, Psychological / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D010879:Piperazines / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D011224:Prazosin / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage
chemical_list: C527165:5-(4-(4-chlorophenyl)piperazin-1-ylmethyl)-1H-indole; D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D050638:Receptors, Dopamine D4; C079049:volinanserin; D003024:Clozapine; D011224:Prazosin
keywords: 5-HT2 receptor; Antipsychotic; D4 receptor; Dopamine; Drug discrimination; Serotonin