Acute and Chronic Effects of Citalopram on 5-HT1A Receptor-Labeling by [18F]MPPF and-Coupling to Receptors-G Proteins

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 [F-18]MPPF were employed, as well as in vitro 8-OH-DPAT-stimulated [S-35]-GTP gamma S binding assay. Additionally, 5-HT1A receptor knockout mice were used to assess the specificity of [F-18]MPPF. Acute treatment with citalopram did not alter [F-18]MPPF binding in dorsal raphe nucleus (DR), frontal cortex, or hippocampus. The absence of [F-18]MPPF binding in the brain of 5-HT1A knock-out mice demonstrates the specificity of MPPF for 5-HT1A receptor brain imaging, but the high affinity of [F-18]MPPF compared to 5-HT suggests that it would only be displaced by dramatic increases in extracellular 5-HT. Chronic citalopram did not modify 5HT(1A) receptor density in any of the brain regions studied. In addition, this treatment did not modify 8-OH-DPAT-stimulated [S-35]-GTP gamma S binding in DR, although a significant increase was observed in frontal cortex and hippocampus. [F-18]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 postsynaptic 5-HT1A receptors. Synapse 63:106-116, 2009. (C) 2008 Wiley-Liss, Inc.