Ameliorating effect of cloperastine on tricyclic antidepressant-resistant depression in rats

Currently used antidepressant drugs are effective in about 70% of patients with depression, but not in remaining about 30% of patients. However, the mechanisms causing treatment-resistant depression are unknown. We have previously reported that cloperastine (CP), a centrally-acting antitussive, has inhibited activation of G protein-coupled inwardly rectifying potassium (GIRK) channels mediated by 5-HT1A receptors in single neurons of the raphe nucleus. This finding seems to indicate that CP might change the level of 5-HT in the brain, because 5-HT1A receptors exist as auto-receptors in the nucleus. Interestingly, CP also ameliorated urinary dysfunctions associated with cerebral infarction, and controlled hyperactivity in an animal model of attention-deficit/ hyperactivity disorder (ADHD). In this study, therefore, we investigated whether or not CP has an antidepressant effect in tricyclic anti depressant-resistant depression model rats which were prepared by ACTH treatment. CP (10, 20 and 40mg/kg, i.p.) caused a dose-dependent reduction of the immobility in the forced swim test, and at a high dose of 40 mg/kg caused an increase in the climbing. Pretreatment with para-chlorophenylalanine (350mg/kg, i.p.), an inhibitor of serotonin synthesis, did not block the ability of CP to reduce immobility. In contrast, alpha-methyl-p-tyrosine (300mg/kg, s.c.), a catecholamine synthesis inhibitor, blocked CP-induced reduction in immobility. Also, CP (20, 40mg/kg, i.p.) reduced the locomotor activity as compared to control. These findings suggest that CP may have an ameliorating effect in an animal model of depressive conditions resistant to antidepressant treatment, and that the effect of CP may be caused by an interaction with noradrenergic and/or dopaminergic system. Further study is undertaken as to whether or not inhibition of GIRK channels might be involved into mechanisms of the effect of CP described here.