This study examined the hypothesis that allelic variants of the ionotropic glutamatergic N-methyl-D-aspartate receptor (NMDAR) are associated with vulnerability to alcoholism and some related traits.
We investigated the silent G2108A and C2664T polymorphisms of the NMDAR1 and the NMDAR2B genes, respectively. The case control study included 367 alcoholic and 335 control subjects of German origin. The family-based study comprised 81 Polish alcoholic patients and their parents using the transmission disequilibrium test.
The genotype frequencies of the NMDAR1 polymorphism differed significantly between control and alcoholic subjects. This difference was also observed in more homogenous subgroups of alcoholic subjects with vegetative withdrawal syndrome and Cloninger type 1. Patients with a history of delirium tremens or seizures during withdrawal showed a significantly increased prevalence of the A allele. Genotyping of the NMDAR2B polymorphism revealed a significantly reduced T allele in Cloninger type 2 alcoholics and in patients reporting an early onset compared with control subjects. Our family-based study for NMDAR2B, revealed a trend to a preferred transmission of the C allele by the fathers, and families with early-onset patients contributed most to this trend.
These results suggest that variants in NMDAR genes are associated with alcoholism and related traits.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Biological Psychiatry
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Reduced ethanol inhibition of N-methyl-D-aspartate receptors by deletion of the NR1 C0 domain or overexpression of α-actinin-2 proteins.J Biol Chem. 2000; 275: 15019-15024
- Calcium influx through NMDA receptors, chronic receptor inhibition by ethanol and 2-amino-5-phosphonopentanoic acid, and receptor protein expression.J Neurochem. 1999; 72: 1969-1980
- Neurogenetic adaptive mechanisms in alcoholism.Science. 1987; 236: 410-416
- Effects of ethanol on ion channels.Int Rev Neurobiol. 1996; 39: 283-367
- Comparison of the effects of the uncompetitive N-methyl-D-aspartate antagonist (±)-5aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCL) with its structural analogs dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures.J Pharmacol Exp Ther. 1992; 260: 1017-1022
- Ethanol withdrawal seizures and the NMDA receptor complex.Eur J Pharmacol. 1990; 176: 289-296
- The genetic epidemiology of alcoholism.in: Begleiter H. Kissin B. The Genetics of Alcoholism. Oxford University Press, Oxford, UK1995: 17-39
- Chronic ethanol treatment produces a selective up-regulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons.Brain Res Mol Brain Res. 1996; 36: 211-218
- The structure of the genetic and environmental risk factor for six major psychiatric disorders in women: Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism.Arch Gen Psychiatry. 1995; 152: 374-383
- The competitive NMDA receptor antagonist, CGP 39551, inhibits ethanol withdrawal seizure.Eur J Pharmacol. 1991; 192: 197-198
- Examination of ethanol, spermine and acamprosate actions on native and recombinant NMDA receptors.Alcohol Clin Exp Res. 2000; 24: 183A
- Mapping of the human NMDAR2B receptor subunit gene (GRIN2B) to chromosome 12p12.Genomics. 1994; 22: 216-218
- A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215
- Fyn-kinase as a determinant of ethanol sensitivity.Science. 1997; 278: 698-701
- Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit. Analysis of association with schizophrenia.Am J Psychiat. 2000; 157: 1329-1331
- Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.Mol Psychiatry. 2001; 6: 211-216
- The novel anti-craving drug acamprosate alters the expression of NMDAR1 splice variant mRNAs in the rat brain.J Neural Transm. 1996; 103: 45-46
- Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients.Mol Psychiatry. 2001; 6: 274-284
- The composite international diagnostic interview. An epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures.Arch Gen Psychiatry. 1988; 45: 1069-1077
- Ethanol inhibition of N-methyl-D-aspartate receptors is reduced by site-directed mutagenesis of a transmembrane domain phenylalanine residue.J Biol Chem. 2001; 276: 44729-44735
- The Mini-International Neuropsychiatric Intervies (MINI).J Clin Psychiatry. 1998; 59: 22-33
- Assessment of ethanol withdrawal.Br J Addict. 1989; 84: 1353-1357
- Evidence for a causative role of N-methyl-D-apartate receptors in an in vitro model of alcohol withdrawal hyperexcitability.J Pharmacol Exper Ther. 1998; 287: 87-97
- The role of glutamatergic neurotransmission in the pathophysiology of alcoholism.Annu Rev Med. 1998; 49: 173-184
- Ethanol and NMDA receptor signaling.Neurobiology. 2000; 14: 69-89
World Health Organization (1992): International classification of diseases. In: Clinical Descriptions and Diagnostic Guidelines, 10th rev ed. Geneva: World Health Organization
Accepted: January 6, 2003
Received in revised form: October 25, 2002
Received: May 30, 2002
© 2003 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.