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The Journal of Neuroscience, June 9, 2004, 24(23):5420-5426; doi:10.1523/JNEUROSCI.0950-04.2004

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Neurobiology of Disease
Acute Treatment with the Antidepressant Fluoxetine Internalizes 5-HT_1A Autoreceptors and Reduces the In Vivo Binding of the PET Radioligand [¹⁸F]MPPF in the Nucleus Raphe Dorsalis of Rat

Mustapha Riad,¹ Luc Zimmer,^2,3 Latifa Rbah,³ Kenneth C. Watkins,¹ Michel Hamon,⁴ and Laurent Descarries¹

¹Departments of Pathology and Cell Biology and of Physiology, and Centre de Recherche en Sciences Neurologiques, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, ²Laboratory of Neuropharmacology, Institut National de la Santé et de la Recherche Médicale (INSERM) U512, Faculty of Pharmacy, Université Claude Bernard, 69366 Lyon, France, ³Centre d'Exploration et Recherche Médicales par Emission de Positons-Animage, Radiopharmacology, Cyclotron Biomédical, 69003 Lyon, France, and ⁴INSERM U288, NeuroPsychoPharmacologie, Faculté deMédecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France

Because 5-HT_1A receptors located on the soma dendrites of serotonin (5-HT) neurons normally mediate an inhibition of 5-HT firing and release, the desensitization of these autoreceptors is essential for obtaining an enhancement of 5-HT transmission after treatment with 5-HT reuptake inhibitors (SSRIs). We have demonstrated previously, using immunoelectron microscopy with specific 5-HT_1A antibodies, that an internalization of 5-HT_1A autoreceptors is associated with their desensitization in rats given a single dose of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Here, we examined the subcellular distribution of 5-HT_1A receptors in dendrites from nucleus raphe dorsalis (NRD) (autoreceptors) and hippocampus (heteroreceptors) after acute treatment with the antidepressant SSRI, fluoxetine (10 mg/kg, i.p.). In parallel experiments, the kinetics of in vivo binding of the 5-HT_1A positron emission tomography radioligand 4,2-(methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]ethylpiperazine ([¹⁸F]MPPF) was measured in these two brain regions by means of stereotaxically implanted microprobes. One hour after treatment, there was a 36% decrease in 5-HT_1A immunogold labeling of the plasma membrane of NRD dendrites, and a concomitant increase in their cytoplasmic labeling, without any change in hippocampal dendrites. In vivo binding of [¹⁸F]MPPF was reduced by 35% in NRD and unchanged in hippocampus. Both effects were blocked by pretreatment with the 5-HT_1A receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide) (1 mg/kg, i.p.). In brain sections of NRD and hippocampus, [¹⁸F]MPPF autoradiographic labeling did not differ between fluoxetine- and saline-treated rats. These immunocytochemical results confirmed that internalization of 5-HT_1A autoreceptors may account for their desensitization, and the microprobe results suggest that this prerequisite for antidepressant treatment efficacy could be amenable to brain imaging in humans.

Key words: SSRI; fluoxetine; 5-HT_1A autoreceptors; internalization; immunogold; [¹⁸F]MPPF

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Received March 15, 2004; revised April 29, 2004; accepted April 29, 2004.

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