L-Arginine abolishes the anxiolytic-like effect of diazepam in the elevated plus-maze test in rats.
The involvement of nitrergic mechanisms in the behavioural effects of diazepam in rats was studied in the elevated plus-maze, open-field and rotarod tests. Administration of the nitric oxide (NO) precursor L-arginine (100 mg/kg, i.p.), assumed to increase the synthesis of NO, abolished the anxiolytic-like effect of diazepam (2 mg/kg, i.p.) in the elevated plus-maze, whereas the inactive enantiomer D-arginine (100 mg/kg) did not. Neither diazepam alone nor in combination with L- or D-arginine affected the exploratory activity of animals in the open field. Pretreatment with L-arginine (100 and 200 mg/kg) did not modify the motor impairment of rats after diazepam (3 mg/kg) in the rotarod test. Diazepam (2 mg/kg i.p.) did not inhibit the cortical or hippocampal cytosolic NO synthase activity measured ex vivo by [3H]L-arginine assay. Diazepam was similarly ineffective in in vitro studies at concentrations up to 10 microM. We conclude that a suppression of NO synthase activity may be important in the anxiolytic-like effect of benzodiazepines. However, diazepam does not inhibit NO synthase directly, but may affect NO synthase activity indirectly via some unknown mechanism.
Volke
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Department of Physiology, University of Tartu, Estonia. vallov@ut.ee
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D003975:Diazepam