Antagonism by NOS inhibition of the behavioral effects of benzodiazepine and GABA_A receptor agonists in the mouse elevated plus-maze

Earlier we implicated nitric oxide (NO) in mediation of the behavioral effects of benzodiazepines. Since benzodiazepines work through facilitation of GABAergic inhibitory neurotransmission, this study was designed to determine whether the direct-acting γ-aminobutyric acid_A (GABA _A) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin- 3-ol) evokes behavioral effects similar to those of benzodiazepines and whether behavioral effects of THIP are also NO dependent. When challenged with either chlordiazepoxide or THIP in an elevated plus-maze paradigm, male NIH Swiss mice exhibited a dose-related increase in open-arm activity. The chlordiazepoxide- induced effects were sensitive to antagonism by a benzodiazepine antagonist, and the effects of THIP were blocked by a GABA_A receptor antagonist. Pretreatment with the NO synthase (NOS) inhibitor L-N^G-nitro arginine antagonized the effects of both chlordiazepoxide and THIP; similar pretreatment with the D-isomer, D-N^G-nitro arginine, which is inactive as an NOS inhibitor, was without effect on chlordiazepoxide and THIP. These findings indicate that chlordiazepoxide and THIP evoke similar behavioral effects in mice in the elevated plus-maze through actions on different parts of the GABA _A receptor, and that NO appears to play a key role in mediation of the behavioral effects of both chlordiazepoxide and THIP.