The Effects of the Nitric Oxide Synthase Inhibitor 7-Nitroindazole on Ethanol Pharmacokinetics in Rats After Acute and Chronic Ethanol Administration

Abstract

The aim of this work was to study the effects of the nitric oxide synthase (NOS) inhibitors 7-nitroindazole (7-NI) and NG-nitro-L-arginine (L-NOARG) on the effects and pharmacokinetics of ethanol in rats. Ethanol at a dose of 4 g/kg, i.p. induced sleep in rats (sleep time: 117.2+/-30.7 min). Administration of the NOS inhibitors 7-NI (20 mg/kg, i.p.) and L-NOARG (20 mg/kg, i.p.) 30 min before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG also significantly increased the toxicity of ethanol as evidenced by increased post-experimental lethality. Ethanol at a dose of 2 g/kg (i.p.) did not induce sleep in vehicle-treated rats; however, the combined administration of ethanol (2 g/kg) and 7-NI at doses of 40, 80, and 120 mg/kg caused sleep, for 49.4+/-3.7, 204.0+/-13.3, and 447.5+/-62.8 min, respectively. L-NOARG (20 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (4 g/kg). 7-NI in lower doses (20 and 40 mg/kg) had no effect and in higher doses (80 and 120 mg/kg) significantly slowed ethanol clearance during the 12 h after ethanol administration. The effect of 7-NI (20 mg/kg) on ethanol pharmacokinetics after chronic ethanol administration (inhalation for 18 days) was also studied. The administration of 7-NI immediately after the end of ethanol exposure had a pronounced effect on ethanol pharmacokinetics; in 7-NI-treated rats the fall in ethanol concentrations was significantly slower as compared with vehicle-treated rats. In 7-NI-treated rats, blood-ethanol levels were higher at 3, 6, 9, and 12 h after the end of ethanol exposure.

The Influence of the Nitric Oxide Synthase InhibitorL‐NOARG on the Effects of Ethanol in Rats after Acute Ethanol Administration

“…This was evidenced by an increase in the duration of ethanol-induced sleep and in the open-field test. These data are in accordance with our previous data where L-NOARG significantly increased the duration of ethanol-induced sleep after acute ethanol administration (4 g/kg, intraperitoneally) (Vassiljev et al 1998a). It is possible that this effect is not caused by interaction of ethanol with nitric oxide pathways but by synergistic CNS depression caused by ethanol and L-NOARG.…”

“…The results of the open-field test are in line with those of De Oliveira et al (1997) where L-NOARG at doses of 30-120 mg/kg decreased exploratory activity in the plusmaze test. In accordance with previous data in the literature (Khanna et al 1995;Calapai et al 1996;Vassiljev et al 1998a) L-NOARG had no effect on ethanol pharmacokinetics. Therefore, these behavioural changes, caused by L-NOARG are not due to pharmacokinetic changes.…”

“…7-Nitroindazole attenuated the behavioural signs of ethanol withdrawal in mice due to pharmacokinetic interaction when administered immediately after the end of ethanol exposure (Vassiljev et al 1998b). L-NOARG also significantly increased the toxicity of ethanol as evidenced by increased post-experimental lethality (Vassiljev et al 1998a) The aim of the present study was to study the influence of L-NOARG on the effects of moderate doses (2 and 3 g/ kg) of ethanol after acute administration.…”

“…7-Nitroindazole also slowed ethanol clearance after acute (at doses of 80 and 120 mg/ kg) and chronic administration (at a dose of 20 mg/kg) (Vassiljev et al 1998a). 7-Nitroindazole attenuated the behavioural signs of ethanol withdrawal in mice due to pharmacokinetic interaction when administered immediately after the end of ethanol exposure (Vassiljev et al 1998b).…”

Influence of drugs acting on nitric oxide-dependent pathways on ethanol tolerance in rats

“…Thus, acute inhibition of NOS induces locomotor sensitization and conditioned place preference to alcohol in DBA/2J mice (Itzhak and Martin 2000), whereas continuous NOS inhibition reduces the responses reinforced by ethanol (Calapai et al 1996;Uzbay et al 1998) and saccharine (Uzbay et al 1998), as well as the ethanol ingestion in rats (Lallemand and De Vitte 1997). Moreover, the hypnotic effect of ethanol is increased by NOS inhibitors and reduced by an NO donor (Adams et al 1994;Vassiljev et al 1998). Similarly, the anxiolytic effect of ethanol was increased by the intrahippocampal microinjection of the preferential neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) and blocked by a similar injection of a cGMP analogue or NO donors (Ferreira et al 1999).…”