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The Journal of Neuroscience, March 15, 2001, 21(6):2178-2185

Functional Consequences of 5-HT Transporter Gene Disruption on 5-HT_1A Receptor-Mediated Regulation of Dorsal Raphe and Hippocampal Cell Activity

Clotilde Mannoury la Cour¹, Claudette Boni¹, Naïma Hanoun¹, Klaus-Peter Lesch², Michel Hamon¹, and Laurence Lanfumey¹

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 Department of Psychiatry, University of Würzburg, 97080 Würzburg, Germany

The consequences of the absence of 5-HT reuptake on the functional properties of 5-HT_1A receptors were examined in the dorsal raphe nucleus and the hippocampus of knock-out mice lacking the serotonin transporter (5-HTT). Extracellular recordings showed that application of selective 5-HT reuptake inhibitors such as paroxetine and citalopram onto brainstem slices resulted in a concentration-dependent inhibition of 5-HT neuron firing in the dorsal raphe nucleus of wild-type 5-HTT+/+ mice, but not 5-HTT/ mutants. By contrast, the 5-HT_1A receptor agonists ipsapirone and 5-carboxamidotryptamine inhibited the discharge in both groups. However, the potency of these agonists was markedly decreased (by ~55- and ~6-fold, respectively) in 5-HTT/ compared with 5-HTT+/+ animals. Similarly, intracellular recordings showed that the potency of 5-carboxamidotryptamine to hyperpolarize 5-HT neurons in the dorsal raphe nucleus was significantly lower in 5-HTT/ than in 5-HTT+/+ animals. These data contrasted with those obtained with hippocampal slices in which 5-carboxamidotryptamine was equipotent to hyperpolarize CA1 pyramidal neurons in both mutant and wild-type mice. As expected from their mediation through 5-HT_1A receptors, the effects of ipsapirone and 5-carboxamidotryptamine were competitively inhibited by the selective 5-HT_1A antagonist WAY 100635 in both groups. These data showed that 5-HTT gene knock-out induced a marked desensitization of 5-HT_1A autoreceptors in the dorsal raphe nucleus without altering postsynaptic 5-HT_1A receptor functioning in the hippocampus. Similarities between these changes and those evoked by chronic treatment with 5-HT reuptake inhibitors emphasize the existence of regional differences in 5-HT_1A receptor regulatory mechanisms.

Key words: 5-HT transporter knock-out mice; 5-HT_1A receptors; dorsal raphe nucleus; hippocampus; desensitization; in vitro electrophysiology

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2162178-08$05.00/0

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