ORIGINAL INVESTIGATION Toluene has antidepressant-like actions in two animal models used for the screening of antidepressant drugs Silvia L. Cruz & Paulina Soberanes-Chávez & Nayeli Páez-Martinez & Carolina López-Rubalcava Received: 24 September 2008 / Accepted: 29 December 2008 / Published online: 17 January 2009 # Springer-Verlag 2009 Abstract Rationale Many abused solvents share a profile of effects with classical antidepressants. For example, toluene, which is a representative and widely abused solvent, has been reported to increase both serotonin and noradrenaline levels in several brain areas after an acute exposure and to act as a noncompetitive antagonist of the glutamatergic N-methyl- D-aspartic acid (NMDA) receptor subtype. Therefore, it is possible that toluene could possess antidepressant-like actions. Objective To provide an initial screening of toluene’ s antidepressant-like actions in the forced swimming test (FST) and the tail suspension test (TST) in mice and to analyze its possible mechanism of action. Materials and methods Two series of experiments were performed. In the first one, male animals were exposed to toluene (0, 500, 1,000, 2,000, or 4,000 ppm) in a static exposure chamber for 30 min, and immediately after, evaluated for antidepressant-like effects. The results were compared with those obtained from mice treated with the serotonergic antidepressant clomipramine (CMI), the nor- adrenergic antidepressant desipramine (DMI), and the glutamatergic antidepressants, ketamine and MK-801. In the second part, we analyzed the effect of a combined administration of a subeffective concentration of toluene with a suboptimal dose of the various antidepressants acting at different neurotransmitter systems. Results Toluene produced a concentration-dependent anti- depressant-like action in the FST and TST and facilitated both MK-801 and ketamine antidepressant-like effects, but not those of DMI or CMI. Conclusions Toluene has antidepressant-like effects that are synergized with NMDA receptor antagonists. Keywords Toluene . Forced swimming test . Tail suspension test Depression is a serious and incapacitating disorder with a heavy social burden and a substantial lifetime risk (Greenberg et al. 2003; Millan 2004). The pathophysiology of depression is not fully understood; however, neurobiolog- ical basic research and clinical studies have shown that the serotonergic and noradrenergic systems are mainly in- volved in the etiology and therapeutics of depression. Because of this, the common basis of pharmacotherapy is based upon the enhancement of these two neurotransmitter systems (Charney 1998; Nemeroff 1998). Recent evidence obtained from preclinical and clinical studies suggests that brain glutamatergic systems could also be involved in depression pathophysiology because compounds that reduce transmission at N-methyl-D-aspartic acid (NMDA) receptors exhibit antidepressant-like actions (Berman et al. 2000; Kudoh et al. 2002; Mathew et al. 2005). Thus, it has been reported that the acute administration of ketamine, a noncompetitive NMDA receptor antagonist, ameliorates depressive symptoms in patients suffering from major depression (Berman et al. 2000; Liebrenz et al. 2007; Zarate et al. 2006). Preclinical findings, which evaluated Psychopharmacology (2009) 204:279–286 DOI 10.1007/s00213-009-1462-2 S. L. Cruz : P. Soberanes-Chávez : C. López-Rubalcava (*) Departamento de Farmacobiologia, Cinvestav, Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, Mexico City C.P. 14330, Mexico e-mail: clopezr@cinvestav.mx Present address: N. Páez-Martinez Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Col. Sto. Tomás, México City 11340, México