title: Acute and chronic effects of citalopram on 5-HT1A receptor-labeling by [18F]MPPF and -coupling to receptors-G proteins.
abstract: Selective serotonin reuptake inhibitors take several weeks to produce their maximal therapeutic antidepressant effect. This delay has been attributed to the gradual desensitization of somatodendritic serotonin 5-HT(1A) autoreceptors. We evaluated adaptive changes of 5-HT(1A) receptors after acute and chronic citalopram challenges in rat. Small animal positron emission tomography trial and quantitative ex vivo autoradiography studies using [(18)F]MPPF were employed, as well as in vitro 8-OH-DPAT-stimulated [(35)S]-GTPgammaS binding assay. Additionally, 5-HT(1A) receptor knock-out mice were used to assess the specificity of [(18)F]MPPF. Acute treatment with citalopram did not alter [(18)F]MPPF binding in dorsal raphe nucleus (DR), frontal cortex, or hippocampus. The absence of [(18)F]MPPF binding in the brain of 5-HT(1A) knock-out mice demonstrates the specificity of MPPF for 5-HT(1A) receptor brain imaging, but the high affinity of [(18)F]MPPF compared to 5-HT suggests that it would only be displaced by dramatic increases in extracellular 5-HT. Chronic citalopram did not modify 5-HT(1A) receptor density in any of the brain regions studied. In addition, this treatment did not modify 8-OH-DPAT-stimulated [(35)S]-GTPgammaS binding in DR, although a significant increase was observed in frontal cortex and hippocampus. [(18)F]MPPF appears to be an efficient radioligand to quantify specifically 5-HT(1A) receptor density in brain imaging. The delayed therapeutic efficacy of citalopram did not appear to be linked to either a downregulation of 5-HT(1A) receptors or to a 5-HT(1A) receptor-G protein decoupling process in serotonergic neurons, but to increased functional sensitivity of postsynaptic 5-HT(1A) receptors.
authors.affiliation: INSERM, Unit U877, J Fourier University, La Tronche, France.
authors.forename: Marcelle
authors.initials: M
authors.lastname: Moulin-Sallanon
authors.forename: Yves
authors.initials: Y
authors.lastname: Charnay
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Pascale
authors.initials: P
authors.lastname: Perret
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Daniel
authors.initials: D
authors.lastname: Fagret
authors.forename: Vicente
authors.initials: V
authors.lastname: Ibáñez
authors.forename: Philippe
authors.initials: P
authors.lastname: Millet
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology*; D005462:Fluorine Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1 / Q000235:genetics / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015283:Citalopram; D005462:Fluorine Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019275:Radiopharmaceuticals; D043562:Receptors, G-Protein-Coupled; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors