title: F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum.
abstract: Brain region-specific modulation of immediate-early gene (IEG) may constitute a marker of antipsychotic drug-like activity. We investigated the effects of the putative antipsychotic drug N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063), a compound that targets both dopamine D(2) and serotonin 5-HT(1A) receptors, in comparison with haloperidol and clozapine on rat mRNA expression of IEG i.e. the zinc-fingered transcription factors c-fos, fosB, zif268, c-jun and junB, two transcription factors of the nuclear receptor family nur77 and nor1, and the effector IEG arc. F15063 (10 mg/kg) and clozapine (10 mg/kg), but not haloperidol (0.63 mg/kg), induced c-fos and fosB mRNA expression in prefrontal cortex, a region associated with control of cognition and negative symptoms of schizophrenia. In striatum, only c-fos, fosB, junB and nur77 were induced by clozapine whereas all IEG mRNAs were increased by haloperidol and F15063 (from 2.5 mg/kg) with similar high efficacy despite a total absence of F15063-induced catalepsy. However, at 0.63 mg/kg, F15063 induced a lower degree of striatal IEG mRNA expression than haloperidol and pretreatment with the serotonin 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY100635) (0.63 mg/kg) increased the level of IEG mRNA induction by F15063. Furthermore, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] at 0.16 mg/kg decreased haloperidol-induced striatal IEG mRNA expression although it exerted no effects on its own. These results are consistent with an activation of serotonin 5-HT(1A) receptors by F15063, thus reducing D(2) blockade-induced striatal IEG mRNA. Furthermore, the substantial F15063-induced expression of IEGs such as c-fos in striatum is not related to cataleptogenic activity and may act more as a marker of efficacious dopamine D(2) receptor blockade.
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, Castres Cedex, France.
authors.forename: Liesbeth A
authors.initials: LA
authors.lastname: Bruins Slot
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lestienne
authors.forename: Catherine
authors.initials: C
authors.lastname: Grevoz-Barret
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000235:genetics*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D001572:Benzofurans; D001596:Benzylamines; D003517:Cyclopentanes; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C518313:N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)ethyl)-3-(cyclopent-1-enyl)benzylamine; D010879:Piperazines; D011725:Pyridines; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D050637:Receptors, Dopamine D3; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D048052:Mitogen-Activated Protein Kinase 3; D003024:Clozapine; D006220:Haloperidol