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

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...

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Published in:European journal of pharmacology 2009-10, Vol.620 (1-3), p.27-35
Main Authors: Bruins Slot, Liesbeth A, Lestienne, Fabrice, Grevoz-Barret, Catherine, Newman-Tancredi, Adrian, Cussac, Didier
Format: Article
Language:English
Subjects:
8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology
Animals
Antipsychotic Agents - pharmacology
Benzofurans - pharmacology
Benzylamines - pharmacology
Clozapine - pharmacology
Cyclopentanes - pharmacology
Dopamine Antagonists - pharmacology
Dopamine D2 Receptor Antagonists
Gene Expression Regulation - drug effects
Genes, Immediate-Early - genetics
Haloperidol - pharmacology
Male
Mitogen-Activated Protein Kinase 3 - genetics
Neostriatum - drug effects
Neostriatum - metabolism
Piperazines - pharmacology
Prefrontal Cortex - drug effects
Prefrontal Cortex - metabolism
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT1A - metabolism
Receptors, Dopamine - metabolism
Receptors, Dopamine D3 - antagonists & inhibitors
RNA, Messenger - genetics
RNA, Messenger - metabolism
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists - pharmacology
Time Factors
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Summary: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.
ISSN:1879-0712
DOI:10.1016/j.ejphar.2009.08.019