ORIGINAL INVESTIGATION Assessing the antidepressant-like effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test Stella Chaviaras & Plato Mak & David Ralph & Lalitha Krishnan & Jillian H. Broadbear Received: 2 January 2010 / Accepted: 19 February 2010 / Published online: 16 March 2010 # Springer-Verlag 2010 Abstract Rationale The distribution of oxytocin receptors in limbic regions, as well as evidence that exogenous oxytocin modu- lates affect and fear processing, suggests that this neuropeptide may have a role to play in the treatment of mood disorders. Objectives This study compared the effects of acute treatment with the oxytocin receptor agonist, carbetocin with the tricyclic antidepressant, imipramine, using male Sprague– Dawley rats. Methods Intracerebroventricular (i.c.v.; 1, 10, 100 μg/rat), intravenous (i.v.; 2.5, 5 mg/kg), and intraperitoneal (i.p.; 2, 6.4, 20 mg/kg) carbetocin and imipramine (1.8, 5.6, 10 mg/kg, i.p.) were examined in the modified forced swim and open field tests. The mechanism of action of carbetocin was investigated by co-administering it with the oxytocin antag- onist, atosiban, either centrally (5 μg/rat, i.c.v.) or systemically (1 mg/kg, i.v.). Results Imipramine and carbetocin (all three routes of administration) both significantly reduced immobility and increased swimming and/or climbing behavior in the forced swim test. The systemic effects of carbetocin were blocked by central and systemic atosiban co-administration. Only am- phetamine (2 mg/kg, i.p.), included as a false positive in order to distinguish whether antidepressant-like effects were due to psychomotor stimulation, increased locomotor activity in the open field test. Conclusions Carbetocin produced antidepressant-like changes in behavior via activation of oxytocin receptors in the CNS. The similarities between imipramine and carbetocin in the forced swim test suggest that drugs which target the oxytocinergic system may aid both the understanding and pharmacological treatment of depressive illness. Keywords Oxytocin . Carbetocin . Forced swim test . Rat . Imipramine . Atosiban . Desmopressin . Antidepressant Abbreviations i.p. intraperitoneal i.c.v. intracerebroventricular i.v. intravenous f.s.t. forced swimming test Introduction The neurohypophyseal peptide oxytocin is best known for its actions in the periphery, which include stimulating milk ejection and uterine contractions (Benoussaidh et al. 2005; Sala et al. 1974). However, there is growing interest in oxytocin’ s role as a neuromodulator in the central nervous system (Sofroniew 1980; Argiolas and Gessa 1991; Landgraf and Neumann 2004), as it is becoming evident that oxytocin is an important modulator of certain behavioral processes such as those which contribute to the expression of mood (Heinrichs et al. 2003; Domes et al. 2007). Aspects of mood for which oxytocin appears to play a modulatory role include the expression of antidepressant- and anxiolytic-like behaviors, as evaluated in both human (Zetzsche et al. 1996; Scantamburlo et al. 2007) and animal studies (Arletti et al. 1995; Arletti and Bertolini 1987; Meisenberg 1982; Nowakowska et al. 2002; Klenerova et al. 2009) and of stress (reviewed in Neumann 2008). Some of oxytocin’ s neuromodulatory effects are thought to be mediated via the serotonergic and noradrenergic systems, S. Chaviaras : P. Mak : D. Ralph : L. Krishnan : J. H. Broadbear (*) School of Psychology and Psychiatry, Monash University, Building 17, Clayton, Vic 3800, Australia e-mail: jillian.broadbear@med.monash.edu.au Psychopharmacology (2010) 210:35–43 DOI 10.1007/s00213-010-1815-x