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The Journal of Neuroscience, November 1, 2001, 21(21):8378-8386

Agonist-Induced Internalization of Serotonin-1A Receptors in the Dorsal Raphe Nucleus (Autoreceptors) But Not Hippocampus (Heteroreceptors)

Mustapha Riad¹, Kenneth C. Watkins¹, Edith Doucet², Michel Hamon², and Laurent Descarries¹

¹ Départements de Pathologie et Biologie Cellulaire et de Physiologie, and Centre de Recherche en Sciences Neurologiques, Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and ² Institut National de la Santé et de la Recherche Médicale U288, Neuropsychopharmacologie, Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France

Serotonin-1A (5-HT_1A) receptors in the CNS are a major target for psychotropic drugs. In nucleus raphe dorsalis (NRD) and hippocampus (CA3), the selective 5-HT_1A agonist (+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) reduces the firing activity of serotoninergic (5-HT) and pyramidal neurons, respectively. When located on 5-HT (autoreceptors), but not on non-5-HT (heteroreceptors) neurons, 5-HT_1A receptors are known to be subject to desensitization. Using quantitative electron microscopy after pre-embedding immunogold labeling with specific antibodies, we examined the subcellular distribution of these receptors after acute administration of 8-OH-DPAT (0.5 mg/kg, i.v.). Silver-intensified immunogold particles associated with the plasma membrane or the cytoplasm were counted in somata and dendrites within the NRD, 15 min, 1 hr and 24 hr after 8-OH-DPAT injection, and in hippocampal dendrites 1 hr after the same treatment. Significant decrease in the density of membrane labeling and concomitant increase of cytoplasmic labeling were demonstrated in the NRD, 15 min and 1 hr after 8-OH-DPAT administration, with a return to baseline level at 24 hr. Internalization was blocked by previous administration of the 5-HT_1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635), which, by itself, was without apparent effect. In hippocampus (CA3), there were no apparent changes in the distribution of the receptor after 8-OH-DPAT administration. These findings are in line with earlier results showing a desensitization of 5-HT_1A autoreceptors but not heteroreceptors after treatment with 5-HT_1A receptor agonist. They suggest that this desensitization is the result of autoreceptor internalization.

Key words: agonist; 5-HT_1A receptors; desensitization; internalization; serotonin; 8-OH-DPAT; nucleus raphe dorsalis; hippocampus; immunocytochemistry

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21218378-09$05.00/0

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