Neuropharmacology 39 (2000) 1984–1995 www.elsevier.com/locate/neuropharm Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated Guillaume Lucas, Philippe De Deurwaerde `re, Gre ´gory Porras, Umberto Spampinato * Laboratoire de Neuropsychobiologie des De ´sadaptations, UMR-CNRS 5541, Universite ´ Victor Segalen Bordeaux 2, Boı ˆte Postale 31, 146, rue Le ´o Saignat, 33076 Bordeaux Cedex, France Accepted 11 January 2000 Abstract In this study, we use in vivo microdialysis to investigate the influence of endogenous serotonin (5-HT) on striatal dopamine (DA) and 5-hydroxyidoleacetic acid (5-HIAA) efflux in both basal and activated conditions. The selective serotonin reuptake inhibi- tors citalopram and fluoxetine were used to mobilize endogenous 5-HT. In halothane-anaesthetized rats, citalopram (5 mg/kg, i.p.), administered either alone or in combination with the 5-HT 1A receptor antagonist WAY 100635 (0.1 mg/kg, s.c.), while reducing striatal 5-HIAA outflow (-25 and -15%, respectively), had no effect on basal DA output. When locally applied into the striatum, citalopram had no effect at 1 μM concentration, but enhanced DA release after its perfusion at 25 and 100 μM concentrations (+ 27% and + 67%, respectively). However, the injection of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, failed to modify the effect of 25 μM citalopram. In freely-moving rats, the intrastriatal infusion of citalopram or fluoxetine (1 μM each), had no effect on its own, but significantly enhanced the increase in DA outflow induced by the subcutaneous administration of 0.01 mg/kg haloperidol (+ 31% and + 30% for citalopram and fluoxetine, respectively). These findings indicate that, in the striatum, endogenous 5-HT has no influence on DA release under basal conditions, but positively modulates DA outflow when nigro-striatal DA transmission is activated.  2000 Elsevier Science Ltd. All rights reserved. Keywords: Microdialysis; Striatum; DA release; 5-HIAA outflow; Endogenous serotonin; Citalopram; Fluoxetine; WAY 100635; Haloperidol; 5,7- DHT; Freely-moving rats; Halothane-anaesthetized rats 1. Introduction It has long been established that serotonin (5-HT) is able to modulate the release of striatal dopamine (DA) in the mammal brain (Besson et al., 1969; Soubrie ´ et al., 1984; Benloucif and Galloway, 1991; Bonhomme et al., 1995; De Deurwaerde `re et al., 1998). The existence of such a control is supported by anatomical data, reporting that 5-HT neurons, mainly located within the dorsal * Corresponding author. Tel.: + 33-557-57-15-44; fax: + 33-556-90- 02-78. E-mail address: umberto.spampinato@lnpb.u-bordeaux2.fr (U. Spampinato). 0028-3908/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(00)00020-4 raphe nucleus (DRN), innervate the nigro-striatal DA system, at both somatodendritic and terminal levels (Dray, 1981; Soghomonian et al., 1989; Moukhles et al., 1997). The exact nature of the influence exerted by 5- HT on striatal DA outflow, however, still remains puz- zling. In vitro studies, using striatal preparations pre- loaded with tritiated DA or its precursor tyrosine, have reported either an inhibitory (Ennis et al., 1981; Westfall and Tittermary, 1982; Muramatsu et al., 1988) or an excitatory (Besson et al., 1969; Yi et al., 1991; Jacocks and Cox, 1992) role for 5-HT on DA release. Conflicting results have also been reported from in vivo microdialy- sis studies. On the one hand, the application of exogen- ous 5-HT into the striatum by reverse microdialysis has been shown to enhance DA output (Benloucif and Gallo- way, 1991; Bonhomme et al., 1995; De Deurwaerde `re