Associate editor: A.L. MorrowN-methyl-d-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability
Introduction
It is an opportune time to consider the contributions of the glutamatergic systems to alcoholism. First, there is a need to explore novel pharmacotherapeutic options for treating ethanol dependence. The established pharmacotherapies for this disorder, disulfiram and naltrexone, show limited efficacy in large multicenter studies Fuller et al., 1986, Krystal et al., 2001. Also, acamprosate (Mason, 2001) and other agents Holter et al., 1996, Holter et al., 2000 that appear to target glutamatergic systems are emerging as additional pharmacotherapeutic agents. Second, preclinical glutamatergic studies now provide an increasingly elaborate understanding of the role of glutamate systems in ethanol actions related to alcoholism Grant & Lovinger, 1995, Woodward, 1999, Krystal & Tabakoff, 2002. Third, the past 5 years marked the emergence of human laboratory studies that have increasingly highlighted the significance of the preclinical research findings for human ethanol abuse and dependence.
This review will employ a translational neuroscience perspective in bridging preclinical and clinical studies that implicate glutamatergic systems in the acute behavioral effects of ethanol, ethanol dependence and withdrawal, treatment of alcoholism, and familial vulnerability to alcoholism. In doing so, it will suggest that (1) the capacity of ethanol to block N-methyl-d-aspartate (NMDA) glutamate receptors is an important component of human ethanol intoxication, (2) ethanol tolerance and dependence and the familial vulnerability to alcoholism are associated with alterations in NMDA receptor function that promote heavy drinking by reducing the negative consequences of ethanol intoxication, (3) acute ethanol withdrawal is associated with increased glutamate release, and (4) glutamatergic agents may play a role as stand-alone or adjunctive treatments for the pharmacotherapy of alcoholism.
Section snippets
N-methyl-d-aspartate receptors
The NMDA receptor is among the highest affinity targets for ethanol in the brain Grant & Lovinger, 1995, Krystal & Tabakoff, 2002. The family of glutamate receptors includes the NMDA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainate ionotropic receptors (i.e., receptors containing a ligand-gated ion channel). It also includes the 8 metabotropic glutamate receptors (mGluR) (i.e., receptors coupled to intracellular signal transduction mechanisms via G-proteins). NMDA
N-methyl-d-aspartate receptor function and reduced sensitivity to ethanol effects
There is compelling preclinical evidence suggesting that adaptations within the brain to chronic ethanol administration contribute to the phenomena of tolerance and withdrawal. In response to the chronic blockade of NMDA receptors associated with sustained ethanol administration, ligand binding to the NMDA receptor is increased, protein levels of the NR1, NR2A, and NR2B subunits rise, and mRNA levels for NR2 subunits increase Trevisan et al., 1994, Kumari & Ticku, 2000.
Factors that reduce the
Glutamatergic dysregulation and the vulnerability to alcoholism
Prior sections of this paper indicated that NMDA receptor contributions to ethanol intoxication, ethanol tolerance, and ethanol dependence that were first identified in animals showed a high degree of applicability to humans. However, it is difficult to know which inbred or genetically engineered rodent strains capture the gene mutations that apply to human alcoholism, regardless of phenotypic similarities between these animals and groups of ethanol-dependent patients. Thus, in attempting to
Summary and implications
Ethanol acts on many cellular targets of several neuromodulators within many neural networks in the brain (Krystal & Tabakoff, 2002). Despite this challenging complexity, the role of NMDA receptors is drawing increasing attention. There is now a convergence of evidence to indicate that (1) NMDA receptors are an important target for ethanol in the brain, (2) ethanol actions at NMDA receptors contribute to its behavioral effects in animals and in humans, (3) ethanol dependence may be associated
Acknowledgements
This work was supported by NIAAA (KO2 AA 00261-01, RO1 AA11321-01A1, and P50 AA99-005) and the Department of Veterans Affairs (Alcohol Research Center, Schizophrenia Biological Research Center, National Center for Post-Traumatic Stress Disorder). The authors thank David Lovinger, PhD and Kathleen Grant, PhD for their helpful comments on an earlier draft of this manuscript.
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