cyclic-gmp and methyl-6-7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate

Several studies have reported the anxiolytic-like effects of various nitric oxide synthase inhibitors in distinct animal models. However, in the context of anxiety, the possible involvement of cyclic GMP, believed to be one of the main targets of NO, remains obscure. Cyclic GMP is degraded by the specific phosphodiesterases in the brain. Therefore, we studied the effect of the selective phosphodiesterase type 5 inhibitor sildenafil in the mouse elevated plus-maze test of anxiety and in the open field test of locomotion. We found that sildenafil (0.05-10 mg/kg i.p.) alone did not affect the behavior of animals in the plus-maze or open field tests, but the anxiogenic beta-carboline DMCM given in a subconvulsive dose (2 mg/kg i.p.) decreased the time spent on open arms in the elevated plus-maze. Treatment with the NO precursor L-arginine (200 mg/kg i.p.) did not modify the behavior of animals in the plus-maze, however, when sildenafil (1 mg/kg i.p.) was administered in combination with L-arginine (200 mg/kg i.p.), both the time spent on the open arms and the percentage of open arm visits were significantly decreased. We conclude that augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Topics: Animals; Anxiety; Arginine; Behavior, Animal; Carbolines; Cyclic GMP; Disease Models, Animal; Drug Therapy, Combination; Injections, Intraperitoneal; Male; Maze Learning; Mice; Motor Activity; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors

The intraperitoneal administration of DMCM (0.5-3 mg/kg) produced a dose-related increase in the content of cyclic GMP in the rat cerebellar cortex. The effect of DMCM on cyclic GMP was abolished by pretreatment with benzodiazepine receptor ligands, diazepam and Ro15-1788 and by the GABA agonist muscimol. The results suggest that DMCM increases cerebellar cyclic GMP content through a direct action on benzodiazepine receptors located in the cerebellar cortex. The interaction between DMCM and the GABAergic system associated with benzodiazepine receptors is discussed. Cerebellar cyclic GMP content can be used as a biochemical index to differentiate agonists and antagonists for benzodiazepine receptors.

Topics: Animals; Benzodiazepinones; Carbolines; Cerebellar Cortex; Cyclic GMP; Diazepam; Dose-Response Relationship, Drug; Flumazenil; Indoles; Male; Muscimol; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, GABA-A; Stimulation, Chemical