Antagonism by NOS Inhibition of the Behavioral Effects of Benzodiazepine and GABAA Receptor Agonists in the Mouse Elevated Plus-Maze

Abstract

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 g-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.

Relations between open‐field, elevated plus‐maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA‐ and 5HT‐anxiolytic agents

“…Chlordiazepoxide enhanced open and open/total arm visits as well as open arm duration, but only in the BALB/c strain, an anxiolytic action found at doses without effect in the open-field. The sensitivity of the elevated plus-maze to the anxiolytic potency of chlordiazepoxide is concordant with findings in BALB/c [19], Swiss [20], Swiss-Webster [22][23][24], and NIH Swiss [21] mice, as well as OF1 mice in the elevated zero-maze [9]. The absence of any effect on C57BL/6J mice at 2.5 and 5 mg/kg is concordant with findings at 7.5 and 15 mg/ kg [22], but not with one positive outcome at 5 mg/kg [19].…”

“…Similar effects have been described in mice. Open arm exploration increased after acute peripheral administration of chlordiazepoxide [19][20][21][22][23][24], diazepam [25][26][27][28][29][30][31], midazolam [32], alprazolam [33], muscimol [26], and valproate [26]. Diazepam was also anxiolytic in mice exposed to the graded anxiety test, an adapted version of the elevated plus-maze with light and dark floors [34].…”

Extrasynaptic GABAA receptor activation reverses recognition memory deficits in an animal model of schizophrenia

“…Both gaboxadol and AA29504 possess anxiolytic properties (Elfline et al 2004;Hoestgaard-Jensen et al 2010), and it could be argued that exploration of novel object could be affected in response to anxiolytic treatment. However, two observations go against this notion.…”

Dissociating anxiolytic and sedative effects of GABAAergic drugs using temperature and locomotor responses to acute stress

“…Generally, the sedative and anxiolytic effects of alcohol were not altered after deletion of the α 1 subunit, suggesting that other yet unexplained factors may play a role (Kralic et al 2003). Moreover, we studied the nonbenzodiazepine hypnotic drug THIP (gaboxadol) that also binds to extrasynaptic GABA A receptor δ subunits with putative anxiolytic effects (Elfline et al 2004; Wafford and Ebert 2006). …”