Short communication Improved efficacy of f luoxetine in increasing hippocampal 5-hydroxytryptamine outf low in 5-HT 1B receptor knock-out mice Isabelle Malagie ´ a , Denis J. David a,b , Pascale Jolliet b , Rene ´ Hen c , Michel Bourin b , Alain M. Gardier a, * a Laboratoire de Neuropharmacologie UPRES EAD MENRT, Faculte ´ de Pharmacie IFR-ISIT Institut de Signalisation et d’Innovation The ´rapeutique, Universite ´ Paris-Sud, Tour D1 2eme etage 5 rue 1-B.Clement, 92296, Cha ˆtenay-Malabry cedex, France b Laboratoire de Pharmacologie, Faculte ´ de Me ´decine, Universite ´ de Nantes, F44035, Nantes cedex 1, France c Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA Received 14 January 2002; received in revised form 8 April 2002; accepted 12 April 2002 Abstract To test for the contribution of the 5-HT 1B receptor subtype in mediating the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), we used intracerebral in vivo microdialysis in awake, freely moving 5-HT 1B receptor knock-out mice. We show that a single systemic administration of fluoxetine (1, 5 or 10 mg/kg, i.p.) increased extracellular serotonin levels [5-HT] ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, fluoxetine, at the three doses studied, induced a larger increase in [5-HT] ext in knock-out than in wild-type mice. In the frontal cortex, the effect of fluoxetine did not differ between the two genotypes. The region-dependent response to fluoxetine described here in mutants confirms data we recently reported for another SSRI, paroxetine. These data suggest that 5-HT 1B autoreceptors limit the effects of selective serotonin reuptake inhibitors on dialysate 5-HT levels at serotonergic nerve terminals located mainly in the ventral hippocampus. Alternative mechanisms, e.g., changes in 5-HT transporter and/or 5-HT 1A receptor density in 5-HT 1B receptor knock-out mice could also explain these findings. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Antidepressant drug, 5-HT 1B autoreceptor; Microdialysis, intracerebral; Knock-out mouse; Fluoxetine; 5-HT (5-hydroxytryptamine, serotonin) reuptake inhibitor, selective 1. Introduction The main hypothesis regarding pathogenesis of major depression involves a deficiency in the brain serotonergic function. In support of this hypothesis, selective serotonin reuptake inhibitors (SSRI), by blocking the transporter of serotonin (5-hydroxytryptamine, 5-HT), increase its synap- tic availability, thus improving the central serotonergic neurotransmission. However, activation of somatodendritic 5-HT 1A and nerve terminal 5-HT 1B autoreceptors by endoge- nous 5-HT seems to limit the therapeutic efficacy of these antidepressant drugs following their acute administration (Gardier et al., 1996). The 5-HT 1B receptor localized in the central nervous system on presynaptic nerve terminals of serotonergic neurons are called autoreceptors because they are involved in a local inhibitory control of 5-HT release (Engel et al., 1986; Maura et al., 1986; Go ¨thert et al., 1987; Pin ˜eyro et al., 1995; Trillat et al., 1997). We recently used intracerebral in vivo microdialysis to investigate the contribution of 5-HT 1B autoreceptors in mediating the effects of a selective serotonin reuptake inhibitor, paroxetine (Malagie ´ et al., 2001). Experiments were performed in awake, freely moving mice lacking 5- HT 1B receptors (5-HT 1B knock-out; Saudou et al., 1994). We demonstrated that a single systemic administration of paroxetine induced a larger increase in extracellular seroto- nin levels [5-HT] ext in the ventral hippocampus of 5-HT 1B receptor knock out than that observed in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose, but not at 5 mg/kg. These results were confirmed by using a receptor antagonist strategy in wild-type mice showing that the blockade of 5-HT 1B receptor with the mixed 5-HT 1B/1D receptor antagonist (N-[4-methoxy-3-(4-methylpiperazin-1- 0014-2999/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S0014-2999(02)01604-7 * Corresponding author. Tel.: +33-1-4683-5416; fax: +33-1-4683-5355. E-mail address: alain.gardier@cep.u-psud.fr (A.M. Gardier). www.elsevier.com/locate/ejphar European Journal of Pharmacology 443 (2002) 99 – 104