Psychopharmacology (1994) 115:59--64 Psychopharmacology © Springer-Verlag 1994 Additive effects of lithium and antidepressants in the forced swimming test: further evidence for involvement of the serotoninergic system M.K. Nixon, M. Hascoet, M. Bourin, M.C.Colombel Laboratoire de Pharmacologie et GIS Medicament, Faculty of Medicine, University of Nantes, 1 rue Gaston Veil, F-44035 Nantes Cedex, France Received: 1 July 1993 / Final version: 23 December 1993 Abstract. In the mouse forced swimming test (FST) pre- treatment with a subactive dose of lithium (1 mEq/kg), given IP 45 min before the test, facilitated the antidepres- sant activity of iprindole, fluoxetine, and moclobemide (given IP 30 min before the test). These antidepressants (ADS) were not active alone in the FST in this study. Moreover, when subactive lithium was combined with a wide range of ADS, each given at subactive doses, those ADS with serotoninergic properties (e.g. imipramine, citalopram, paroxetine, fluoxetine, trazodone, mianserin, and moclobemide) significantly reduced immobility times. ADS acting primarily on noradrenaline (NA) or dopamine (DA) systems (desipramine, maprotiline, vilox- azine, and bupropion) did not significantly decrease im- mobility when given in combination with lithium. This was also the case for RO 16 6491 [a reversible, B specific monoamine oxidase inhibitor (MAOI)], nialamide, and pargyline (both irreversible, mixed MAOIs). The anti-im- mobility effect of iprindole in combination with lithium suggests either a direct or indirect action on the serotonin (5HT) system by this ADS whose mechanism of action remains obscure. These results, using an animal behav- ioral model of depression and combining our present knowledge of the acute action of various ADS, support the hypothesis that the potentiation by lithium of ADS is via direct 5HT mechanisms,indirectly via a NA/5HT link, and/or by second messenger systems. Lithium may also facilitate the expression of antidepressant activity of ADS not active by themselves in the FST. Key words: Lithium - Antidepressants ....... Serotonin - Forced swimming test - Mice An enhancement of serotonin (5HT) mediated synaptic transmission has been suggested by De Montigny and colleagues as the therapeutic mode of action of potentia- tion of antidepressants by lithium in patients with refrac- Correspondence to: M. Bourin tory depression (De Montigny et al. 1981). Chronic ad- ministration of iprindole and tricyclic antidepressants in rats produces a sensitization of postsynaptic serotonin receptors, apparently unrelated to presynaptic uptake mechanisms (De Montigny and Aghajanian 1978). Gra- hame-Smith and Green (1974) showed that enhanced hy- peractivity in rats treated with lithium was mediated by the enhanced efficacy of 5HT neurons. Short term lithium administration has been shown to enhance 5HT neuro- transmission through its presynaptic action on 5HT ter- minals (Blier and De Montigny 1985), but also to have a sensitizing effect on a sub-set of postsynaptic 5HTIA re- ceptors (De Montigny and Blier 1992). Previous work using mice in the forced swimming test (FST), an animal model of depression introduced by Porsolt et al. (1977), has shown that clonidine, an alpha2 agonist, potentiates subactive doses of numerous antidepressants (ADS) when given in a subactive dose itself. The ability of clonidine to render subactive doses of 5HT reuptake in- hibitors active suggested an interrelationship in activity between 5HT and NA systems (Malinge et al. 1988). Bourin et al. (1991) demonstrated that the effect of clonidine on antidepressants in the FST was specific, as no additive effect was noted with non-antidepressants except for certain dopaminergic drugs which have antide- pressant properties. More recently, 5HT1A agonists have been investigat- ed, using animal models, with regard to their antidepres- sant action (Cervo et al. 1988; Martin et al. 1990). Using the same methodology as Malinge (1988), several 5HTIA agonists were given in combination with clonidine or lithium, all at subactive doses, using the forced swimming test (Hascoet et al. 1994). Not all 5HTaA agonists were affected equally. Ipsapirone and gepirone showed antide- pressant profiles with the addition of clonidine and lithi- um, respectively. From these experiments it could be con- cluded that both clonidine and lithium might be useful adjuncts in screening antidepressants using the FST. In this experiment, the aim was systematically to test antidepressants from different categories, based on their neurochemical mechanism of action, using a behavioral