Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test. Imipramine (10 and 30 mg kg−1, i.p.) and amitriptyline (5 and 15 mg kg−1, i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)‐α‐methylhistamine, at a dose (10 mg kg−1, i.p.) which did not modify the cumulative time of immobility. The histamine H3 receptor antagonist, thioperamide (2–20 mg kg−1, s.c.), showed an antidepressant‐like effect, with a maximum at the dose of 5 mg kg−1, which was completely prevented by (R)‐α‐methylhistamine. The histamine‐N‐methyltransferase inhibitor, metoprine (2–20 mg kg−1, s.c.), was effective with an ED50 of 4.02 (2.71–5.96) mg kg−1; its effect was prevented by (R)‐α‐methylhistamine. The histamine precursor, l‐histidine (100–1000 mg kg−1, i.p.), dose‐dependently decreased the time of immobility ED30 587 (499–712) mg kg−1. The effect of 500 mg kg−1 l‐histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)‐α‐fluoromethylhistidine (50 mg kg−1, i.p.), administered 15 h before. The highly selective histamine H1 receptor agonist, 2‐(3‐trifluoromethylphenyl)histamine (0.3–6.5 μg per mouse, i.c.v.), and the better known H1 agonist, 2‐thiazolylethylamine (0.1–1 μg per mouse, i.c.v.), were both dose‐dependently effective in decreasing the time of immobility ED50 3.6 (1.53–8.48) and 1.34 (0.084–21.5) μg per mouse, respectively. None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test. It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant‐like effect, via activation of H1 receptors. British Journal of Pharmacology (1998) 123, 1331–1336; doi:10.1038/sj.bjp.0701740