Antidepressant-like effect of coadministration of sulpiride an fluvoxamine in mice Yukio Ago a , Toshiya Harasawa a , Soichi Itoh a , Shigeo Nakamura a , Akemichi Baba b , Toshio Matsuda a, ⁎ a Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka,Japan b Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka,Japan Received 9 May 2005; received in revised form 2 August 2005; accepted 8 August 2005 Available online 2 September 2005 Abstract We have recently reported that coadministration of sulpiride, an antipsychotic drug, and fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, selectively increases in vivo dopamine release in the prefrontal cortex. This study examined the effec of these drugs on duration of immobility in the tail suspension test using mice. Neither sulpiride (3 or 10 mg/kg) nor fluv mg/kg) alone affected immobility time, whereas coadministration significantly reduced immobility time. WAY100635, a 5-HT 1A receptor antagonist, did notaffectthe effects of sulpiride and fluvoxamine coadministration, butreduced immobility time in combination with fluvoxamine (20 mg/kg). A high dose offluvoxamine alone (60 mg/kg) also reduced immobility time. These results suggest thatthe antidepressant-like effects of fluvoxamine in combination with sulpiride or WAY100635 in the tail suspension test are mediated by the activation of dopamine or 5-HT systems, respectively. © 2005 Elsevier B.V. All rights reserved. Keywords: Tail suspension test; Sulpiride; Fluvoxamine; Antidepressant; WAY100635 1. Introduction Enhancement of central serotonergic function underlies the therapeuticeffectsof selectiveserotonin(5-HT) reuptake inhibitors (SSRIs), which have become the most used class of antidepressant agents.However,many individuals experience depressive episodes that are resis- tantto SSRI treatment (Barbuiand Hotopf, 2001;Ferrier, 1999;Nelson,1999).Clinicalstudiesshow thatatypical antipsychotics suchasrisperidoneandolanzapineare effective when added to an SSRI in cases ofdepression whereSSRI treatment aloneis ineffective(treatment- resistant depression) (O'Connorand Silver, 1998;Ostroff and Nelson, 1999;Shelton etal., 2001).To clarify the neurochemical mechanisms underlying this clinical effect, Zhang et al. (2000) and Koch et al. (2004) examined the effectsof combinations of atypicalantipsychotics and SSRIs on monoamine levels in rat prefrontal cortex. The results demonstrated that a combination of olanzapine w fluoxetine produces robust,sustained increases in extra- cellulardopamine, noradrenaline and 5-HT levels in rat prefrontal cortex.This findingsuggests that prefrontal monoamineneurotransmitters may contributeto the clinical effect of combination therapyusing atypical antipsychotics and an SSRI. We have recently examined the effects of coadministe ing the typical dopamine D 2 receptor antagonist sulpiride and the SSRI fluvoxamineon prefrontalmonoamine release,to studythe role of dopamineD 2 receptor blockade in the combination effect (Ago et al., 2005). Our study revealed that coadministration of sulpiride at 3 10 mg/kg and fluvoxamine at 10–20 mg/kg causes a selective increase in prefrontal dopamine release in rats. This findingsuggests thatthe combinationmayhave antidepressant effects, given previous reports that various European Journal of Pharmacology 520 (2005) 86 – 90 www.elsevier.com/locate/ejphar * Corresponding author. Tel.: +81 6 6879 8161; fax: +81 6 6879 8159. E-mail address: matsuda@phs.osaka-u.ac.jp (T. Matsuda). 0014-2999/$ - see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.08.011