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, 3 (4), 281-97

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

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

József Nagy et al. Curr Neuropharmacol.

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.

Keywords: Alcohol; NMDA receptor; NR2B subunit selective antagonist; dependence; pharmacotherapy; withdrawal.

Figures

Fig. (1)
Fig. (1)
Drug dependence as neuroadaptation. The concept is that the administration of a drug acutely “unbalances” the chemistry of the brain. In order to overcome this effect, the brain institutes a homeostatic mechanism, i.e. an “opposing neuroadaptation” that balances the effect of the drug on brain chemistry. While the drug is present in the brain, the system remains in relative balance (i.e. there is evidence of drug tolerance). However, rapid removal of the drug now exposes the adaptation because it is no longer “balanced” by the drug. The resulting functional disturbance is the cause of the drug withdrawal syndrome. In Himmelsbach’s theory, this will continue until the adaptation can be removed and the chemistry of the brain returns to its normal balancing act. Collier’s modification of this hypothesis was to propose that, since drugs act on receptors in the brain, it was logical to suppose that a primary mechanism for neuroadaptation to drugs would be to regulate the numbers of those receptors. This type of adaptation would reduce the effects of the drug, but would also cause alterations when the drug left the brain because the natural transmitters inside the brain also use the same receptors. This modified unitary, hypothesis remains implicitly accepted by neuropharmacologists today, but we are beginning to recognize that it represents a gross oversimplification of the complex cellular mechanisms for drug dependence. From: John Littleton. (2001) Receptor regulation as a unitary mechanism for drug tolerance and physical dependence—not quite as simple as it seemed! Addiction 96, 87–101.
Fig. (2)
Fig. (2)
Schematic diagram of NMDA receptor ion channel. Diagram representing NMDA receptor ion channel with its various regulatory sites. The receptor is activated by agonists such as glutamate or NMDA. APV is a competitive antagonist, 5,7-di-Cl-KYN binds to a strychnine insensitive glycine site, ifenprodil is a polyamine site antagonist. The open NMDA channel is blocked by Mg2+ and by uncompetitive antagonists such as MK-801. Glycine and D-serine act as coagonists. Additionally, polyamines and Zn2+ ions modulate the NMDA receptor. There are phosphorylation sites (P) that modulate responses of the receptor to agonists and may play a role in synaptic plasticity. Each subunit is believed to have four regions (I, II, III, and IV) within the cell membrane From: Bisaga, A. and Popik, P. (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug Alcohol Depend. 59, 1–15.
Fig. (3)
Fig. (3)
Toxic effect of 24 h ethanol-withdrawal and its inhibition by re-addition of ethanol in ethanol pre-treated primary cortical cultures. A) LDH activity of the culture medium expressed as percentage of total activity was measured in cultures pre-treated with different concentrations of ethanol once for 24 or 72 hours as well as daily for 3 successive days. B) Inhibition of alcohol-withdrawal induced cytotoxicity by readdition of ethanol in primary cultures of rat cortical neurones pretreated with 100 mM ethanol daily for 3 successive days. (*: p<0.05, **: p<0.01, ***: p<0.001 as compared to the respective control not treated with ethanol) From: Nagy J., László L. (2002) Increased sensitivity to NMDA is involved in alcohol-withdrawal induced cytotoxicity observed in primary cultures of cortical neurones chronically pre-treated with ethanol. Neurochem. Int., 40, 585–591.
Fig. (4)
Fig. (4)
Altered excitotoxic effect of NMDA after ethanol pretreatment. Effect of acute and chronic ethanol treatment on NMDA induced cytotoxicity. Control cortical cultures (squares) and cortical cultures pre-treated with 100mM ethanol repeatedly, once daily for 3 days (circles) were exposed to 300 μM NMDA for 15 min in the presence (open symbols) or absence (closed symbols) of 100 mM ethanol. LDH-release, expressed as percentage of total LDH content, was measured 24 h after NMDA wash out. (*, P<0.01 compared to NMDA induced LDH-release in control cultures; #, P<0.01 compared to LDH-release in absence of ethanol).
Fig. (5)
Fig. (5)
Effect of chronic ethanol pre-treatment on the expression of different NMDA receptor subunits and NR1 splice cassettes. Primary cortical and hippocampal cultures were treated with 100 mM ethanol daily for 3 days. Fixed samples were incubated in the presence of different NR2 and NR1 splice variant specific primary antibodies (Novus Biologicals). The binding of the primary antibodies was visualised via FITC-conjugated secondary antibodies (Sigma). Intensity of the subunit specific fluorescent labelling was analysed using a FACScan flow cytometer. The arithmetic mean FITC-fluorescence intensities were calculated from fluorescence histograms. The mean fluorescence values from samples incubated with the given NMDA receptor subunit specific antibody (NR staining) were corrected with the fluorescence of samples stained with an isotype specific control antibody (background). Each column represents the percentage of corrected fluorescence values obtained from ethanol pre-treated vs. control cultures. (Each value represents mean + S.E. (bars); *: p<0.05, **: p<0.01, ***: p<0.001 compared to the control, paired t-test). Data from: Nagy, J., Kolok, S., Dezso?, P., Boros, A. Szombathelyi, Z. (2003) Differential alterations in the expression of NMDA receptor subunits following chronic ethanol treatment in primary cultures of rat cortical and hippocampal neurones. Neurochem. Int., 42(1), 35-43.
Fig. (6)
Fig. (6)
Inhibitory effect of NMDAR antagonists on ethanolwithdrawal-induced neurotoxicity. Neuronal cell death caused by 24-hour ethanol-withdrawal in primary cultures of rat cortical neurones pre-treated with 100 mM ethanol for 3 consecutive days was quantified by measuring LDHrelease. Different concentrations of MK-801, erythro-ifenprodil and acamprosate (panel A) or some known (open symbols, dashed lines) and novel (filled symbols, straight lines) NR2B SSNAs (panel B) were present during the withdrawal period. Each point represents the percentage of inhibition (mean ± S.E. (error bars)). From: Nagy, J., Horváth, C., Farkas, S., Kolok, S., Szombathelyi, Z. (2004) NR2B subunit selective NMDA antagonists inhibit neurotoxic effect of alcohol-withdrawal in primary cultures of rat cortical neurones. Neurochem. Int., 44(1), 17-23.

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