The few available data on the pharmacological effect of 5-HT5A receptors suggest that antagonists may have anxiolytic, antidepressant and antipsychotic activity. The aim of our study was to verify these suggestions in relevant animal models. Two 5-HT5A antagonist ligands, SB-699551-A (N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride) (3-60 mg/kg, intraperitoneally) and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine) (3-30 mg/kg, intraperitoneally), were examined in the open-field test, in a foot-shock-induced ultrasonic vocalization test, in the forced swim test (FST) and in the amphetamine-induced and phencyclidine-induced hyperlocomotion tests to examine their effect on general behavioural patterns, and their anxiolytic-like, antidepressant-like and antipsychotic-like properties, respectively. In the open-field test, SB-699551-A induced sedation and A-843277 induced writhing. In the ultrasonic vocalization test, SB-699551-A reduced vocalizations, whereas A-843277 was ineffective. In the FST, SB-699551-A was ineffective and A-843277 reduced immobility, but only at the highest dose. In the amphetamine-induced and phencyclidine-induced hyperlocomotion test, both compounds were ineffective. SB-699551-A showed an anxiolytic-like property in the ultrasonic vocalization test; however, this compound has a sedative effect. A-843277 showed an antidepressant-like property in the FST, but its immobility-reducing effect may also be a consequence of abdominal irritation. Consequently, further investigations are required to define the therapeutic potential of 5-HT5A receptor ligands in anxiety, depression and schizophrenia models.