Antidepressant effect of low dose nimodipine in the mouse behaviour despair model

摘要

Dihydropyridine Calcium Channel Blockers (DHP-CCB) have been reported to exert conflicting effects in various experimental models of depression. We observed the effect of centrally acting DHP-CCB, nimodipine at various doses in behaviour despair model using Porsolt’s Forced Swim Test in mice. Nimodipine showed significant antidepressant activity only at 2.5 mg/kg given intraperitoneally. A possible therapeutic window phenomenon is thought to come to play at lower doses of the drug. Thus nimodipine can be developed as a strong weapon and added to the armamentarium used especially against cerebrovascular diseases where the possibility of depression setting in can not be ruled out. Introduction Calcium channel blockers of the dihydropyridine class (DHP-CCB) like nifedipine, nitrendipine, and nimodipine have been reported to reduce immobility in the mouse behavioural despair model of depression in the dose of 0.1, 1.0, and 10 mg/kg i.p., and co-administration of antidepressant potentiates the effect of nifedipine (Mogilnicka et al., 1987). In another study, in a dose of 5 mg/kg i.p., nimodipine did not affect the immobility but nifedipine or nitrendipine reduced the immobility time in the same dose (Czyrak et al., 1989). It was further reported that there was no significant decrease in immobility time of rats in the forced swim test treated with nimodipine in the dose of 10 mg/kg i.p. or compared to tricyclic antidepressants (Czyrak et al., 1990).Although nifedipine and nitrendipine seemed to consistently decrease the immobility time in rats and mice, nimodipine seemed to have variable actions at different doses and in different animal species. Nimodipine, unlike other CCB-DHP is centrally acting approved for its use in ischemic stroke and sub-arachnoid haemorrhage (Tettenborn et al., 1985). Apart from these, there are other roles which have been attributed to nimodipine including as an analgesic (Filos et al., 1993), anti-platelet agent (Feinberg and Bruck, 1993), as a cognition enhancer, and to prevent migraine attacks. A potential role as an antidepressant is still questionable.Considering this diversity of reports, we examined the effect of nimodipine in various doses (1.25, 2.5, 5, 10, and 20 mg/kg i.p.) in the behaviour despair model in mice and compared it with standard antidepressant amitriptyline for its potential antidepressant action. Materials and methods AnimalsSwiss albino mice weighing 23-28 g were selected for the procedure. Animals were housed in our laboratory with 12 hour light and dark cycle along with adequate food and water for at least 1 week prior to the study. The experiment was performed between 10 a.m.-4 p.m. i.e. during the light phase of the day.DrugsThe drugs used in the study were; nimodipine as a test drug and amitriptyline as positive control. As both the drugs are insoluble in water, 1% tween-20 was used to make their suspension. The suspension was freshly prepared and was protected from direct sun light. Mother solution of nimodipine was later titrated down to attain various calculated doses (1.25, 2.5, 5, 10, and 20 mg/kg).Apparatus and test procedureWater tub of 60 cm (inner diameter) and 35 cm (height) was used. It was filled with water (27-29 °C) up to a height of 15 cm. For the evaluation of drugs, we used Porsolt’s Forced Swim Test (Porsolt et al., 1977). It was a 2 day procedure. On day 1, each animal was dropped in water and was forced to swim for 6 min. It was then wiped dry and returned to home cage. On day 2, mice were injected (intraperitoneal; i.p.) with various doses of the test and control drug. After a gap of 1 hour they were subjected to the swim test. In accordance with Porsolt et al, mice were kept in water for 6 min. First, animals make vigorous attempt to climb and come out of water. Later, realizing the futility of the attempts, they give up. In between, the animals stops making any attempts to swim or come out of water and it only moves that much, what is required of them t