Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Abstract

Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

Altered Relation Between Lipopolysaccharide‐Induced Inflammatory Response and Excitotoxicity in Rat Organotypic Hippocampal Slice Cultures During Ethanol Withdrawal

“…Most evidence supports two possible mechanisms that are not exclusionary. One is that ethanol exposure upregulates the number of N-methyl-D-aspartate receptors (NMDAR) (Follesa and Ticku, 1996) and/or changes their subunit composition (Nagy et al, 2003), resulting in hypersensitive conformations of the receptor (Nagy et al, 2005). The second is that release of glutamate (Rossetti et al, 1999) and polyamines (Gibson et al, 2003) is greater during EWD, resulting in the overactivation of NMDARs.…”

Functional polymorphisms of the glutamate receptor N-methyl D-aspartate 2A gene are associated with heroin addiction

“…GRIN2A knockout mice show increased spontaneous locomotor activity and deficits in contextual fear conditioning and spatial learning, as well as reduced hippocampal long-term potentiation (Sakimura et al, 1995) thought to be involved in addiction (Squire, 1992). Several studies showed that chronic administration of drugs of abuse, such as alcohol (Nagy et al, 2005), methamphetamine (Simoes et al, 2008), cocaine (Ben-Shahar et al, 2009), and nicotine (Wang et al, 2007), alters GRIN2A activity in the brain, suggesting that the GRIN2A gene is an excellent candidate target for treating addiction disorders. These studies suggest that GRIN2A is closely associated with drug addiction and is a key mediator of the pathogenesis of drug addiction.…”

Analysis of Variations in the Glutamate Receptor, N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

“…Moreover, GRIN2A knockout mice failed to show evidence of conditioned place preference, suggesting an impairment in learned reward-related responses to ethanol [16]. Several studies have shown that chronic administration of drugs of abuse, such as alcohol [17], methamphetamine [18], cocaine [19], and nicotine [20], alters the activity of GRIN2A in the brain, suggesting that the GRIN2A gene is an excellent candidate target for treatment of addiction disorders. Importantly, these results indicate that glutamatergic transmission, particularly through GRIN2A-containing NMDA receptors in the nucleus accumbens, probably contributes to the development of opiate addiction and confirms the hypothesis that subtype-selective NMDA receptor antagonists may be beneficial in the treatment of opiate addiction and withdrawal [21].…”