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Work supported by grants SAF 2007-62378, FIS PI060264 and Pierre Fabre Medicament. L.L.-P. is supported by a JAE fellowship from CSIC. P.C. is supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya. We acknowledge Veronique Ravailhe and Christelle Benas for technical assistance with microdialysis experiments and Monica Gutierrez and Veronica Paz for electrophysiological experiments.

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Artigas, FCorresponding AuthorCelada, PAuthor

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September 15, 2024
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Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors

Publicated to:British Journal Of Pharmacology. 160 (8): 1929-1940 - 2010-08-01 160(8), DOI: 10.1111/j.1476-5381.2010.00738.x

Authors: Llado-Pelfort, L; Assie, M-B; Newman-Tancredi, A; Artigas, F; Celada, P

Affiliations

CSIC, IIBB, IDIBAPS, Dept Neurochem & Neuropharmacol, Barcelona 08036, Spain - Author
Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain - Author
Ctr Rech Pierre Fabre, Neurobiol Div 2, F-81106 Castres, France - Author
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain - Author

Abstract

Background and purpose: F15599, a novel 5-hydroxytryptamine (5-HT)(1A) receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors. Experimental approach: In vivo single unit and local field potential recordings and microdialysis in the rat. Key results: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 mu g center dot kg-1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses > 10-fold higher (minimal effective dose 8.2 mu g center dot kg-1 i.v.). Both effects were reversed by the 5-HT1A antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (similar to 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 mu g center dot kg-1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 mu g center dot kg-1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (+/-)WAY100635. Conclusions and implications: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.

Keywords

3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone5-ht1a receptorsAction potentialsAnimalsAntidepressive agentsAntipsychotic agentsAutoreceptorsBay x 3702BrainComplicationsCyclohexanesCytologyDepressionDopamineDopamine antagonistsDopamine releaseDorsaDose-response relationship, drugDysfunctionElectrophysiological evidenceHippocampusImpairmentInjections, intraperitonealLocal field potentiaMaleMedial prefrontal cortexMemoryMetabolismMicrodialysisMicrodialysis, local field potentialMidbrain-raphePiperazinesPiperidinesPrefrontal cortexPyramidal cellsPyramidal neuronesPyramidal neuronsPyrimidinesRaphe nucleiRat-brainRating-scaleRatsRats, sprague-dawleyRats, wistarReceptor, serotonin, 5-ht1aSchizophreniaSerotonergic neuronsSerotoninSerotonin 5-ht1 receptor agonistsSerotonin 5-ht1 receptor antagonistsSerotonin receptor agonistsSerotonin(1a) receptorsSynapsesTime factorsTrialWay 101363

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal British Journal Of Pharmacology due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2010, it was in position 19/252, thus managing to position itself as a Q1 (Primer Cuartil), in the category Pharmacology & Pharmacy.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 10.06, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-02, the following number of citations:

  • WoS: 95
  • Scopus: 83
  • Europe PMC: 50

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-02:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 85 (PlumX).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Llado-Pelfort, L) and Last Author (Celada Pedrosa, María Paz).

the author responsible for correspondence tasks has been Artigas Perez, Francesc.