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The Journal of Neuroscience, July 1, 2000, 20(13):5065-5075

Homeostatic Regulation of Serotonergic Function by the Serotonin Transporter As Revealed by Nonviral Gene Transfer

Véronique Fabre¹, Benjamin Boutrel¹, Naïma Hanoun¹, Laurence Lanfumey¹, Claude Michelle Fattaccini¹, Barbara Demeneix², Joëlle Adrien¹, Michel Hamon¹, and Marie-Pascale Martres¹

¹ Institut National de la Santé et de la Recherche Médicale U288, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France, and ² Laboratoire de Physiologie Générale et Comparée, Unité de Recherche Associée 90, Centre National de la Recherche Scientifique, Museum National d'Histoire Naturelle, 75231 Paris Cedex 5, France

With the aim of exploring the relationship between the serotonin transporter (5-HTT or SERT) and the activity level of serotonin (5-HT) neurotransmission, in vivo expression of this protein was specifically altered using a nonviral DNA transfer method. Plasmids containing the entire coding sequence or a partial antisense sequence of the 5-HTT gene were complexed with the cationic polymer polyethylenimine and injected into the dorsal raphe nucleus of adult male rats. Significant increase or decrease in both [³H]citalopram binding and [³H]5-HT synaptosomal uptake were observed in various brain areas up to 2 weeks after a single administration of the sense plasmid or 7 d after injection of the short antisense plasmid, respectively. Such changes in 5-HTT expression were associated with functional alterations in 5-HT neurotransmission, as shown by the increased capacity of 5-HT_1A receptor stimulation to enhance [³⁵S]GTP--S binding onto the dorsal raphe nucleus in sections from rats injected with the sense plasmid. Conversely, both a decrease in 5-HT_1A-mediated [³⁵S]GTP--S binding and a reduced potency of the 5-HT_1A receptor agonist ipsapirone to inhibit neuronal firing were observed in the dorsal raphe nucleus of antisense plasmid-injected rats. Furthermore, changes in brain 5-HT and/or 5-HIAA levels, and sleep wakefulness circadian rhythm in the latter animals demonstrated that altered expression of 5-HTT by recombinant plasmids has important functional consequences on central 5-HT neurotransmission in adult rats.

Key words: nonviral gene transfer; 5-HT transporter-encoding plasmids; polyethylenimine; dorsal raphe nucleus; 5-HT_1A receptor; 5-HT turnover; sleep

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20135065-11$05.00/0

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