Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice

Abstract

The present study examined the roles of NR2A and NR2B subunit-containing NMDA receptors in the mediation of the sedative/hypnotic effects of ethanol in mice. The ability of the competitive NMDA antagonist, CGP-37849 (0, 1, or 3 mg/kg), and the NR2B-selective antagonist, Ro 25-6981 (0, 3, or 10 mg/kg), to alter (3 g/kg) ethanol-induced sleep time was measured in C57BL/6J mice and NR2A knockout (KO) mice. The results show that pretreatment with either antagonist significantly potentiated the sedative/hypnotic effects of ethanol in C57BL/6J mice. These effects were not significantly altered in NR2A KO mice. Basal sleep time responses to ethanol were also normal in NR2A KO mice. These findings confirm a major role for NMDA receptors in the acute intoxicating actions of ethanol and provide tentative support for a prepotent role of the NR2B subunit in these effects.

Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit

“…Replicating and extending our earlier finding, NR2A KO mice showed normal sensitivity to the sedative/hypnotic effects of ethanol (Boyce- Rustay and Holmes 2005). There was a significant effect of ethanol dose (F2,37=121.94, P<.01) but not of genotype (ns) and no dose×genotype interaction (ns) for sleep time responses to ethanol.…”

“…Ethanol-induced sedation/hypnosis was assessed as previously described (Boyce- Rustay and Holmes 2005). The mouse was injected with 3 or 4 g/kg and placed into the supine position in a "V"-shaped chamber.…”

“…NMDA receptor channel blockers and competitive antagonists, but not NR2B-selective or glycine B antagonists, decrease ethanol self-administration and can substitute for ethanol in discrimination studies (Bienkowski et al 1999;Grant and Colombo 1993;Hundt et al 1998;Piasecki et al 1998;Rassnick et al 1992;Sanger 1993;Shelton and Balster 1997). On the other hand, competitive, noncompetitive, and NR2B-selective antagonists all increase sensitivity to the sedative/hypnotic effects of ethanol (Boyce- Rustay and Holmes 2005;Silveri and Spear 2002), but noncompetitive antagonists do not affect ethanol-induced hypothermia (Khanna et al 1997).…”

Ethanol Inhibits Clearance of Brain Serotonin by a Serotonin Transporter-Independent Mechanism

“…The hypnotic/sedative effects of ethanol were assessed by measuring sleep time, as described previously (Crabbe et al, 1981;Boyce-Rustay and Holmes, 2005). 5-HTTϩ/ϩ, ϩ/Ϫ, and Ϫ/Ϫ mice were placed in the supine position in "V"-shaped chambers immediately after intraperitoneal injection of 3.0 or 4.0 g/kg of ethanol (200 proof prepared in 0.9% saline to produce 20% v/v solutions).…”

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

“…Little is known, however, about the effects that acute ethanol administration has on neuronal function in this region. The N-methyl-D-asparate receptor (NMDAR) has been heavily implicated in the acute actions of ethanol in both behavioral (Boyce-Rustay and Holmes, 2005) and molecular studies (Roberto et al, 2004). NMDARs in the BNST have been specifically implicated in the regulation of stress and anxiety Pawlak et al, 2005), which have been suggested to be important in regulating ethanol-seeking behavior in humans and in animal models of alcohol drinking.…”