Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats.
The forced swimming test (FST) has been extensively used as a screening model for new antidepressant agents. It has been shown that drugs which reduce the amount of nitric oxide (NO) have the same outcome in this model as classic antidepressants. In addition, previous studies have shown that methylene blue, which acts as a direct inhibitor of both NOS and soluble guanylate cyclase (sGC), mimics the effect of clinically effective antidepressants in patients and in the FST. The present study examined the effects of the specific inhibitor of the NO-sGC pathway, [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one] (ODQ) and of the neuronal NOS inhibitor 7-nitroindazole (7-NI) in the FST. We found that ODQ (10 and 20 mg/kg) significantly decreased the immobility time in the FST compared to the control. Similarly, injections of 7-NI (30 or 60 mg/kg) reduced immobility time as well as Imipramine (IMI, 30 mg/kg). Interestingly, L-Arginine (250 mg/kg) administered in combination with ODQ reversed the effect of ODQ but displayed no effect when administered alone. Locomotion activity was significantly decreased following administration of IMI (30 mg/kg) and 7-NI (30 and 60 mg/kg) but was unaffected after administration of ODQ (10 and 20 mg/kg). These findings suggest that the NO-sGC-cGMP pathway may play an important role in the mediation of the behavioural effect in the FST without influence on motor activity.
Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Skovagervej 2, DK-8240 Risskov, Denmark.
Ida Louise
IL
Heiberg
Gregers
G
Wegener
Raben
R
Rosenberg
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D003863:Depression / Q000523:psychology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D007099:Imipramine / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming / Q000523:psychology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D007191:Indazoles; D010069:Oxadiazoles; D011810:Quinoxalines; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D007099:Imipramine; C080122:7-nitroindazole; D004121:Dimethyl Sulfoxide