Neuroscience Letters 490 (2011) 191–195 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Tramadol increases extracellular levels of serotonin and noradrenaline as measured by in vivo microdialysis in the ventral hippocampus of freely-moving rats P. Bloms-Funke a,∗ , E. Dremencov b , T.I.F.H. Cremers b , T.M. Tzschentke a a Grünenthal GmbH, Global Preclinical Research and Development, 52099 Aachen, Germany b Brains-on-Line, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands article info Article history: Received 13 October 2010 Received in revised form 7 December 2010 Accepted 21 December 2010 Keywords: Tramadol Serotonin Noradrenaline Microdialysis Brain Rat abstract Tramadol is an atypical opioid with monoamine re-uptake inhibition properties. The aim of the current study was to compare, using in vivo microdialysis, the effect of tramadol on extracellular serotonin (5- HT) and noradrenaline (NA) levels in the rat ventral hippocampus with the effects of the dual 5-HT/NA inhibitors (SNRIs) duloxetine and venlafaxine, the tricyclic antidepressant clomipramine, the selective 5-HT re-uptake inhibitor (SSRI) citalopram, and the selective NA re-uptake inhibitor (NRI) reboxetine. It was found that tramadol, duloxetine and venlafaxine increased extracellular levels of both, 5-HT and NA, in a dose-dependent manner. Clomipramine also increased extracellular 5-HT and NA levels, however not dose-dependently in the tested dose range. Citalopram selectively increased extracellular 5-HT levels. Reboxetine increased extracellular NA levels and also to a minimal degree 5-HT levels. It can be concluded that, albeit less efficacious, the effects of tramadol on serotonergic and noradrenergic neurotransmission resemble those of the dual 5-HT and NA re-uptake inhibitors duloxetine, venlafaxine, and clomipramine, and are different from those of the SSRI citalopram and the NRI reboxetine. © 2011 Elsevier Ireland Ltd. All rights reserved. Tramadol is a racemate whose two enantiomers have distinct phar- macological properties: (+)-tramadol inhibits 5-HT re-uptake, and (-)-tramadol inhibits NA re-uptake [11,22]. The major metabo- lite of both enantiomers of tramadol is O-desmethyl-tramadol, the product of oxidation by the hepatic enzyme cytochrome P450 2D6. The (+)-enantiomer of this metabolite is a potent agonist of -opioid receptors [13,21]. Thus, the 5-HT and NA re-uptake inhibition properties of tramadol are due to the (+)- and (-)- enantiomers of the parent drug, respectively, and the -opioid action of tramadol is due to the (+)-enantiomer of its major metabo- lite O-desmethyl-tramadol. Tramadol’s ability to inhibit monoamine re-uptake and thereby increase extracellular monoamine concentrations in brain tissue has been shown in numerous in vitro and ex vivo studies using synaptosomes or slice preparations from specific rat brain regions [1,9–12]. These studies suggest interactions of tramadol with the Abbreviations: NA, noradrenaline (norepinephrine); 5-HT, serotonin (5- hydroxytryptamine); SNRI, dual 5-HT/NA inhibitor; SSRI, selective 5-HT re-uptake inhibitor; NRI, selective NA re-uptake inhibitor; LC, locus coeruleus; DRN, dorsal raphe nucleus. ∗ Corresponding author at: Grünenthal GmbH, Global Preclinical Research and Development, Zieglerstrasse 6, D-52099 Aachen, Germany. Tel.: +49 241 569 2697; fax: +49 241 569 1228. E-mail address: Petra.Bloms-Funke@grunenthal.com (P. Bloms-Funke). noradrenergic and the serotonergic systems which, albeit with lower potencies [5,16], resemble that of dual 5-HT/NA re-uptake inhibitory antidepressant drugs. An earlier in vivo microdialysis study with tramadol showed that a high dose of tramadol (75 mg/kg i.p.) elevates extracellular dopamine levels in the rat nucleus accumbens [24]; however, 5-HT and NA levels were not assessed in that study. Munro et al. [17] demonstrated that tramadol increases 5-HT and NA levels in the rat hippocampus. The increase in 5-HT levels was dose-dependent. However, again only very high doses of tramadol were used in this study (57 and 100 mg/kg s.c.). The mechanistic interpretation of the effects of tramadol on extracellular 5-HT and NA levels is complicated by the fact that - opioids can also influence levels of these monoamines [15,29], and a similar effect of (+)-O-desmethyl-tramadol cannot be excluded. The aim of the present study was to assess the effects of different doses of tramadol on 5-HT and NA levels in the rat ventral hippocampus and to compare these to the effects of antide- pressant drugs, such as the dual 5-HT/NA re-uptake inhibitors (SNRIs) duloxetine and venlafaxine, the tricyclic antidepressant drug clomipramine, the selective 5-HT re-uptake inhibitor (SSRI) citalopram, and the selective NA re-uptake inhibitor (NRI) reboxe- tine. Although the effects of these antidepressants on hippocampal 5-HT and NA levels have been studied previously by a number of groups [6,14,16], one purpose of the present study was to compare 0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2010.12.049