Acute and chronic effects of citalopram on 5-HT1Areceptor- 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-HT1A autoreceptors. We evaluated adaptive changes of 5-HT1A receptors after acute and chronic citalopram challenges in rat. Small animal positron emission tomography trial and quantitative ex vivo autoradiography studies using [18F]MPPF were employed, as well as in vitro 8- OH-DPAT-stimulated [35S]-GTPγS binding assay. Additionally, 5-HT1A receptor knockout mice were used to assess the specificity of [ 18F]MPPF. Acute treatment with citalo- pram did not alter [ 18F]MPPF binding in dorsal raphe nucleus (DR), frontal cortex, or hippocampus. The absence of [18F]MPPF binding in the brain of 5-HT1Aknock-out mice demonstrates the specificity of MPPF for 5-HT1A receptor brain imaging, but the high affinity of [ 18F]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- HT1A receptor density in any of the brain regions studied. In addition, this treatment did not modify 8-OH-DPAT-stimulated [ 35S]-GTPγS binding in DR, although a significant increase was observed in frontal cortex and hippocampus. [18F]MPPF appears to be an efficient radioligand to quantify specifically 5-HT1A receptor density in brain imaging. The delayed therapeutic efficacy of citalopram did not appear to be linked to either a downregulation of 5-HT1A receptors or to a 5-HT1A receptor-G protein decoupling process in serotonergic neurons, but to increased functional sensitivity of postsy- naptic 5-HT1A receptors. © 2008 Wiley-Liss, Inc.