These authors contributed equally to this work.
NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol
Article first published online: 15 AUG 2011
© 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society
Genes, Brain and Behavior
Volume 10, Issue 7, pages 805–816, October 2011
How to Cite
Badanich, K. A., Doremus-Fitzwater, T. L., Mulholland, P. J., Randall, P. K., Delpire, E. and Becker, H. C. (2011), NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol. Genes, Brain and Behavior, 10: 805–816. doi: 10.1111/j.1601-183X.2011.00720.x
- Issue published online: 9 OCT 2011
- Article first published online: 15 AUG 2011
- Accepted manuscript online: 18 JUL 2011 12:00AM EST
- Received 30 January 2011, revised 29 April 2011 and 21 June 2011, accepted for publication 6 July 2011
- locomotor activity;
- loss of righting;
- NMDA receptor
The NR2B subunit of N-methyl d-aspartate glutamate receptors influences pharmacological properties and confers greater sensitivity to the modulatory effects of ethanol. This study examined behavioral responses to acute ethanol in a conditional knockout mouse model that allowed for a delayed genetic deletion of the NR2B subunit to avoid mouse lethality. Mice lacking the NR2B gene (knockout) were produced by mating NR2B[f/f] mice with CAMKIIa-driven tTA transgenic mice and the tetO-CRE transgenic mice. Adult male and female offspring representing each of the resultant genotypes (knockout, CAM, CRE and wildtype mice) were tested for open-field locomotor activity following acute low- and high-dose ethanol challenge as well as loss of righting reflex. Findings indicate that male and female mice lacking the NR2B subunit exhibited greater overall activity in comparison to other genotypes during the baseline locomotor activity test. NR2B knockout mice exhibited an exaggerated stimulant response to 1.5 g/kg (i.p.) and an exaggerated depressant response to 3.0 g/kg (i.p.) ethanol challenge. In addition, NR2B knockout mice slept longer following a high dose of ethanol (4.0 g/kg, i.p.). To evaluate pharmacokinetics, clearance rates of ethanol (1.5, 4.0 g/kg, i.p.) were measured and showed that female NR2B knockouts had a faster rate of metabolism only at the higher ethanol dose. Western blot analyses confirmed significant reduction in NR2B expression in the forebrain of knockout mice. Collectively, these data indicate that the NR2B subunit of the N-methyl d-aspartate glutamate receptor is involved in regulating low-dose stimulant effects of ethanol and the depressant/hypnotic effects of ethanol.