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Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; 2009.

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Biology of the NMDA Receptor.

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Chapter 4The NMDA Receptor and Alcohol Addiction

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4.1 INTRODUCTION

Alcohol addiction is a costly and detrimental chronic relapsing disorder, characterized by compulsive alcohol use despite the negative consequences; it is thought to be associated with aberrant learning and memory processes [1,2]. The NMDA-type glutamate receptor (NMDAR) plays an essential role in synaptic plasticity and learning and memory [3,4]. Not surprisingly, it is well established that the NMDAR is a major target of alcohol (ethanol) in the brain and has been implicated in ethanol-associated phenotypes such as tolerance, dependence, withdrawal, craving, and relapse [5,6]. This chapter focuses on studies elucidating molecular mechanisms that underlie ethanol’s actions on the NMDAR, and discusses the physiological and behavioral consequences of ethanol’s actions. Finally, we summarize information regarding the potential use of modulators of NMDAR function as medication to treat the adverse effects of alcoholism.

4.2 ACUTE ETHANOL INHIBITION OF NMDA RECEPTOR FUNCTION

In 1989, Lovinger et al. reported that ethanol (5–100 mM) acutely inhibits NMDA-activated ion currents in cultured mouse hippocampal neurons [7]. The inhibitory actions of ethanol on the activity of the channel were further demonstrated by measuring NMDAR-mediated excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in slices from many brain regions such as the hippocampus [8–13], cortex [8,13–15], amygdala [16,17], nucleus accumbens [18,19], and dorsal striatum [20–22], as well as in mammalian heterologous expression systems such as HEK cells and Xenopus oocytes expressing recombinant NMDARs. The reduction in NMDAR activity upon acute exposure to ethanol is concentration-dependent and has a very rapid (less than 100 ms) onset when measured in NMDA-evoked currents using a fast solution exchange technique [14,23,24].

Single channel recordings in cultured cortical neurons revealed that ethanol decreases the open channel probability and mean open time of native NMDARs [8]. The precise mechanism by which ethanol rapidly inhibits NMDAR function is still under investigation. However, the very fast reduction of channel activity in response to ethanol suggests a direct interaction of the NMDAR subunits with ethanol to regulate channel gating in nonneuronal mammalian cell culture models such as HEK-293 cells, as well as Xenopus oocytes transfected with different combinations of NMDAR subunits that are commonly used to determine ethanol sensitivity to a defined subunit composition and/or amino acid substitution of specific amino acids, as described below.

4.2.1 The NR1 Subunit

The NR1 subunit is encoded from one gene. However, the subunit contains three sites of alternative splicing, one in the N-terminus and two in the C-terminus [25]. This results in a total of eight possible splice variants. The C-terminus of the NR1 subunit is made of four cassettes (C0, C1, C2, and C2') [26], and the C0 cassette is present in all splice variants. The C0 cassette is an important mediator of the inhibitory actions of ethanol on the function of the channel, as deletion of the C0 cassette is reported to reduce the potency of ethanol-mediated inhibition of NMDAR activity [27]. However, this deletion seems to affect only NR1/NR2A, but not NR1/NR2B or 2C combinations [27,28]. In addition, several studies have suggested that amino acids within the third and fourth transmembrane domain of the subunit confer the channel’s sensitivity to ethanol [29,30].

4.2.2 NR2 Subunits

Both NR2A- and NR2B-containing NMDARs are highly sensitive to the inhibitory actions of ethanol and are thought to be more sensitive to ethanol than those containing NR2C or NR2D subunits [31–33]. However, comparison of the degree of ethanol sensitivity of NR2A- and NR2B-containing receptors remains inconclusive. For example, NR2B-containing receptors were found to be more sensitive to ethanol compared to NR2A-containing ones [34], but opposite results were also reported [32,33]. However, when comparing the sensitivities of different NR2 subunit-containing NMDARs to ethanol, it is important to note that the different NR1 splice variants may also affect the sensitivity of a specific NR2 subunit-containing NMDAR to ethanol. For example, Jin and Woodward tested (in transfected HEK 293 cell) the effect of ethanol exposure on 32 possible NMDARs consisting of 1 of 8 NR1 splice variants and 1 of 4 NR2 subunits. The maximal inhibition of channel activity in the presence of ethanol was observed in NR1-2b/NR2C, while the minimal one was found in NR1-3b/NR2C, NR1-3b/NR2D, and NR1-4b/NR2C [35]. No single NR1 splice variant or NR2 subunit showed a consistently high or low degree of ethanol inhibition when combined with other NR2 subunits or NR1 splice variants [35]. These findings suggest that the overall sensitivity of an individual NMDAR to ethanol depends on specific combinations of NR1 and NR2 subunits. Finally, several amino acids within the third and fourth transmembrane domains of the NR2A subunit have been identified as residues that contribute to the inhibitory actions of ethanol on the activity of the channel [30,36–38]. However, whether or not point mutations in the NR2B subunit affect ethanol sensitivity is yet to be determined.

In summary, the studies described above provide important information on the mechanism of the fast inhibitory action of ethanol on the activity of the channel. However, as these studies were obtained from nonneuronal systems, the results should be further confirmed in more physiologically-relevant systems.

4.2.3 Cofactors

Cofactors that contribute to the activity of the NMDAR, such as magnesium and zinc ions, as well as the amino acid glycine, may also play a role in the molecular mechanism mediating ethanol’s action on the activity of the channel. However, the contribution of cofactors to the modulation of NMDAR activity by ethanol remains unclear.

Mg2+

Extracellular Mg2+ voltage-dependently blocks the NMDAR channel by binding to a deep site of the channel pore [39,40]. In hippocampal slices, the IC50 of ethanol inhibition of NMDAR activity was reported to be ~50 and ~100 mM in the presence of 1 and 0 mM Mg2+, respectively, suggesting that low Mg2+ reduces the sensitivity of NMDARs to ethanol [10,41]. In amygdala slices, 44 mM ethanol inhibits NMDAR-mediated EPSCs in 1 mM Mg2+ by 30%, but loses its inhibition in 0.3 mM Mg2+, and increases in NMDAR EPSCs in the presence of ethanol were observed in 0 Mg2+, suggesting again that low Mg2+ reduces the sensitivity of NMDARs to ethanol [16]. However, these results remain controversial, as other groups reported that Mg2+ does not affect the degree of ethanol inhibition of NMDAR response. For example, in hippocampal slices, ethanol inhibition of NMDAR response was reported to be similar in normal Mg2+ (1.5 mM) and low-Mg2+ (0.1 mM) solutions [9]. In oocytes expressing NR1/NR2A, NR1/NR2B, or NR1/NR2C, the presence of high (3 mM) or low (0.01 mM) Mg2+ does not alter ethanol sensitivity of NMDARs [31]. In cultured hippocampal neurons, Mg2+ was also found not to affect ethanol inhibition of NMDA-activated currents [42].

Glycine —

The glycine binding site is located within the NR1 subunit [43–45]. Although some studies reported that glycine modulates ethanol inhibition of NMDAR function [46–51], other studies have not found evidence to support this finding [31, 32,42,52–56].

Zn2+

In HEK-293 cells expressing NR1 and NR2A subunits, chelation of Zn2+ by EDTA reduced ethanol inhibition of NMDAR activity [57,58]. However, such an effect was not observed in another study [31].

4.2.4 Posttranslation Modifications

Posttranslation modifications such as phosphorylation–dephosphorylation events, which occur in a time frame of minutes after ethanol exposure, also contribute to the inhibitory actions of ethanol on the NMDAR. For example, we found that exposure of hippocampal slices to ethanol results in the internalization of NR2A-containing receptors via a mechanism that depends on activation of the small G protein H-Ras and inhibition of the tyrosine kinase Src [59]. We further showed that as a result of ethanol-mediated internalization of the channel, the contribution of NR2A to the activity of the channel is decreased [59].

In addition, Alvestad et al. reported that acute ethanol treatment of hippocampal CA1 slices decreased the basal level of tyrosine phosphorylation of NR2A and NR2B subunits, and that the phosphotyrosine phosphotase inhibitor bpV reduced ethanol inhibition of NMDAR-mediated field EPSPs in hippocampal slices [60]. As tyrosine phosphatases contribute to both the activation and inhibition of the phosphorylation and activity of NMDAR [61], it is likely that a tyrosine phosphatase contributes to the acute effects of ethanol on NMDAR response.

4.3 FACILITATION OF NMDA RECEPTOR FUNCTION BY ETHANOL

4.3.1 Acute Tolerance of NMDA Receptors to Ethanol Inhibition

As stated above, the primary acute effects of ethanol on NMDAR activity is inhibition. However, in some brain regions the inhibitory effect of ethanol is reduced as a function of time. This acute decrease in the sensitivity of NMDARs to ethanol inhibition is termed “acute tolerance,” and was first described by Grover et al. in rat hippocampal slices, in which a significant decrease in ethanol inhibition was observed over a 15-minute period of ethanol exposure [62]. Acute tolerance to ethanol’s inhibitory actions on NMDAR function was later confirmed in both mouse and rat hippocampal slices [13,59,63].

In addition, Li et al. showed that in spinal cord slices ethanol depressed NMDAR activity by ~37% at 8–10 minutes, but only ~17% at 20 minutes. Neurons in other brain regions including the nucleus locus creruleus [64], the basolateral amygdala [16], and rostral ventrolateral medulla [65] also show similar phenotypes of acute tolerance of NMDAR activity to ethanol inhibition.

An interesting question is whether or not the tolerance will eventually counteract the inhibitory effect of ethanol. The answer appears, at least in some preparations, to be positive. For example, in hippocampal CA1 slices, we previously observed that the NMDAR activity returns to its basal level after 35 minutes of ethanol application [13]. Similarly, in rostral ventrolateral medulla neurons, ethanol inhibition was not detected 40 minutes after ethanol exposure [65].

4.3.2 Rebound Potentiation and Long-Term Facilitation of NMDA Receptor Activity

We (and others) observed that in various brain regions and in the spinal cord, the activity of the channel is greatly potentiated upon ethanol washout [13,21,66–69], and even low concentrations of ethanol (10 mM) were shown to induce such potentiation [69]. In addition, we recently observed that in dorsal striatal slices, acute ethanol exposure and withdrawal results in long-term facilitation (LTF) of NMDAR-mediated EPSCs [21], and a phenomenon similar to LTF was also detected in spinal cord slices [66–69], in rostral ventrolateral medulla neurons slices [65], and in locus ceruleus neurons slices [64].

4.3.3 Molecular Mechanisms Mediating Facilitation of NMDA Receptor Function by Ethanol

The NR2 subunits are phosphorylated by the Src family protein tyrosine kinases (PTKs) Fyn and Src [61], leading to upregulation of channel function [61]. In 1997, Miyakawa et al. [63] observed that NR2B phosphorylation is increased after ethanol administration in Fyn heterozygous (Fyn+/−) but not in Fyn deletion (Fyn−/−) mice, and that acute tolerance to ethanol inhibition of NMDAR-mediated field EPSPs was observed in hippocampal slices from Fyn+/− but not from Fyn−/− mice. These results suggest a role for Fyn kinase in acute tolerance of NMDAR activity.

Several years later we identified a molecular mechanism that underlies this phenotype. We found that in the hippocampus, the scaffolding protein RACK1 localizes Fyn kinase to the NR2B subunit; [70] however RACK1 acts as a negative modulator to prevent NR2B phosphorylation by Fyn kinase [70]. Activation of the cAMP/PKA pathway leads to dissociation of the trimolecular complex allowing Fyn kinase to phosphorylate NR2B, which, in turn, leads to an increase in channel function [71,72]. Importantly, we found that exposure of hippocampal slices to ethanol leads to the dissociation of RACK1 from the Fyn/NR2B complex via a mechanism that requires activation of the cAMP/PKA pathway, leading to phosphorylation of NR2B [13].

Our results further suggest that this mechanism accounts for the development of acute tolerance in the presence of ethanol, and to the rebound potentiation upon ethanol washout. We found that when the Src PTK inhibitor, PP2, was applied to the hippocampal slice preparation prior to ethanol washout, the rebound potentiation was not observed, and when the inhibitor was applied at the peak of the rebound potentiation, a rapid inhibition of NMDAR activity was observed [13]. Furthermore, when recombinant RACK1 was added to the hippocampal slice preparation, ethanol-mediated NR2B phosphorylation was inhibited and acute tolerance was not observed [13]. Taken together, these results suggest that Fyn phosphorylation of the NR2B subunit is, at least in part, the mechanism that accounts for the enhancement of the activity of the channel in the hippocampus in response to ethanol exposure.

As mentioned above, in the dorsal striatum, acute ethanol exposure and withdrawal leads to prolonged enhancement of NMDAR-mediated EPSCs upon ethanol washout [21]. Here, too, treatment with ethanol leads to NR2B phosphorylation both ex vivo in slice preparations and in vivo, and the corresponding RACK1 dissociation from the trimolecular complex leading to the activation of Fyn kinase [21]. Interestingly, both Fyn activation and NR2B phosphorylation were observed after ethanol washout. Importantly, the LTF of NMDAR-EPSCs was not observed in the presence of the Fyn inhibitor PP2, in dorsal striatal slices from Fyn−/− mice, or upon incubation of dorsal striatal slices with the selective NR2B-containing NMDAR inhibitor Ro 25-6981 [21].

Taken together, these results suggest that this mechanism of Fyn kinase dissociation from RACK1, leading to its activation and to NR2B phosphorylation, accounts for the rebound potentiation and to LTF of NMDAR activity after ethanol exposure in the hippocampus and dorsal striatum, respectively.

Finally, the metabotropic glutamate receptor [67] and PKCγ [68] were found to be required for the development of acute tolerance and withdrawal potentiation, respectively, in the spinal cord. Specifically, Li et al. observed that the extent of ethanol inhibition of NMDAR activity is reduced from ~37% at 8–10 minutes to ~17% at 20 minutes, and that such reduction is enhanced by the metabotropic glutamate receptor agonist ACPD and is attenuated by the antagonist MCPG, suggesting that acute tolerance of NMDAR activity to ethanol in the spinal cord is developed in a metabotropic glutamate receptor-dependent manner [67].

Also, in spinal cord slices, Li et al. found that the NMDAR activity is potentiated by ~24% at 18 minutes after a 15-minute ethanol application, and that such potentiation is prevented by bath application of a PKCγ inhibitory peptide γV5-3, indicating that withdrawal potentiation in the spinal cord develops via a PKCγ-dependent manner [68].

4.3.4 Brain Region-Specific Actions of Ethanol

Interestingly, ethanol does not affect NMDAR function at all brain regions identically. For instance, an in vivo study showed that in the inferior colliculus and the hippocampus, but not in the lateral septum, ethanol inhibited NMDA-induced neuronal activity [73]. An ex vivo imaging study showed that Ca2+ influx through NMDARs in neurons from brainstem was not affected by concentrations of ethanol as high as 160 mM [74]. Interestingly, the sensitivity of the NMDAR subunits to posttranslation modifications upon ethanol exposure is also not universal throughout the brain.

We observed that in the hippocampus or the dorsal striatum, acute exposure to ethanol resulted in an increase in the tyrosine phosphorylation of the NR2B subunit of the NMDAR, leading to the upregulation of channel function, but none of these phenotypes were observed in the prefrontal cortex or ventral striatum [13,21]. We found that Fyn is compartmentalized to the NR2B subunit of the NMDAR only in the hippocampus and the dorsal striatum, but not in the ventral striatum or the prefrontal cortex [13, 21], suggesting that brain region specificity to ethanol’s actions results, at least in part, from differences in the intracellular compartmentalization of signaling and scaffolding proteins.

4.3.5 Chronic Ethanol and Synaptic Compartmentalization of NMDA Receptor Subunits

Elegant studies conducted by Chandler and colleagues showed that prolonged exposure of hippocampal neurons with moderate doses of ethanol resulted in clustering of NMDARs in dendritic spines, and the clustering was found to be restricted to synaptic but not extrasynaptic pools of the receptor [75]. These changes were blocked by a PKA inhibitor, and by a low dose of a NMDAR antagonist [75]. In addition, the authors observed that the enhanced synaptic localization on NMDARs required the postsynaptic density scaffolding protein, PSD-95 [76]. Finally, these changes were correlated with an increase in synaptic NMDAR currents [75]. Interestingly, a recent study by Offenhauser and colleagues showed that acute exposure of cerebellar granule cells to high concentrations of ethanol resulted in the redistribution of F-actin away from postsynaptic sites. The study further suggests that the cytoskeletal remodeling induced by ethanol depends on the NMDAR and actin binding protein Esp8 [77]. Although acute ethanol exposure inhibits NMDAR function and thus prevents long-term plasticity such as LTP (see below), prolonged ethanol exposure employs an adaptive process, such as increasing the trafficking of NMDARs to synapses [75]. As calcium influx through NMDARs evokes AMPAR insertion via a calcium/calmodulin-dependent protein kinase II-dependent process [78], prolonged ethanol exposure would be expected to reduce the clustering of AMPARs in synapses. However, increased trafficking of NMDARs to the synapses may counterbalance the ethanol inhibition of NMDAR activity, leading to no changes in synaptic AMPAR clustering [75].

4.3.6 Chronic Ethanol Exposure and Withdrawal Alters NMDA Receptor Function

Exposure to ethanol for 24 hours or longer followed by withdrawal has been shown to lead to hyperactivation of the channel in neuronal preparations [79]. For example, withdrawal from chronic exposure of cultured hippocampal slices to ethanol (35 mM or 70 mM) for 5 to 11 days increased the NMDAR activity that occurs within 1 hour after ethanol was removed and lasted for at least 7 hours [80,81].

In vivo studies showed that withdrawal from exposure of rats to continuous ethanol vapor for at least 2 weeks increased the contribution of the NR2B subunit to NMDAR function [82]. However, such a change was not observed 1 week after withdrawal from chronic ethanol exposed rats [83]. One explanation for the hyperexcitability of the NMDAR upon withdrawal from chronic ethanol exposure is an increase in number of receptors resulting from an adaptation mechanism that is due to the long lasting inhibition of activity of the channel.

To test this possibility, Ticku et al. and others used primary neurons exposed chronically (several days) to ethanol to determine whether the expression level of the NMDAR subunits was altered. The investigators observed that chronic ethanol treatment upregulated the mRNA level of the NR2B subunit [84,85], and protein levels of the NR1 and NR2B subunits [86]. More recently, increases in NR2B gene AP-1 binding and promotor activity were observed upon chronic exposure of cortical neurons to ethanol, suggesting a mechanism for the increase in NR2B expression in response to ethanol [87]. Another possible mechanism mediating the increase in mRNA levels in response to ethanol was reported by Qiang et al., who showed that ethanol exposure leads to a decrease in the mRNA level of the NR2B transcriptional repressor NRSF (neuro-restrictive silencer factor) [88]. Kumari et al. investigated the molecular mechanism underlying the increase in the expression of the NR1 subunit and found an enhancement of NR1 mRNA stability upon chronic exposure to ethanol [89], possibly via an association with the RNA binding protein GIIβ [90]. They also found that the protein levels of NR1, NR2A, and NR2B were elevated in rat hippocampal and cortical neurons exposed chronically to ethanol ex vivo and in vivo [86,91–93]. In addition, chronic intermittent exposure of cortical neurons to ethanol resulted in a significant increase in both the message and protein levels of the NR2B subunit [94]. Taken together, these results confirm the hypothesis that hyperexcitability of the NMDAR channel upon chronic ethanol exposure and withdrawal is due to an increase in the mRNA and protein levels of NMDAR subunits. Interestingly, Pawlak et al. showed that the serine protease tissue plasminogen activator (tPA) contributes to the upregulation of NR2B-containing NMDARs upon ethanol exposure and to ethanol withdrawal syndrome. The authors reported that tPA-deficient mice have a decreased severity of seizures upon ethanol withdrawal that corresponds with a reduction in NR2B level. The authors further showed that tPA increased ethanol withdrawal seizures, whereas an NR2B-NMDAR selective antagonist reversed tPA’s effect [95].

4.4 PHYSIOLOGICAL IMPLICATIONS OF MODULATION OF NMDA RECEPTOR FUNCTION BY ETHANOL

4.4.1 Acute Inhibition

It is well known that the NMDAR plays a key role in long-term potentiation (LTP) of the AMPAR-mediated synaptic response, which is a cellular model of learning and memory [3,4]. As expected, inhibition of NMDARs by ethanol was reported to also block hippocampal LTP [96–98], which was more pronounced in juvenile rats (30 days old) than in adult rats (90 days old) [99]. In addition, such inhibition has also been observed in vivo. Givens et al. reported that in awake rats, LTP was produced by stimulation of electrodes implanted in the dentate gyrus of the hippocampus, and this LTP was inhibited by intraperitoneal injection of nonintoxicating doses of ethanol (0.5 or 1.0 g/kg) given prior to the LTP induction [100]. Ethanol inhibition of LTP was observed not only in the hippocampus but also in other brain regions. NMDAR-dependent LTP in the dorsomedial striatum [101] was recently reported to be abolished by ethanol at concentrations as low as 10 mM [20]. LTP in the dorsolateral bed nucleus was also shown to be inhibited by ethanol [102]. LTP is a cellular model of learning and memory [4,103], and in humans, ethanol disrupts performance on a variety of short-term memory tasks [104–106] and ethanol inhibition of LTP may be associated with drinking-induced blackouts [107]. Finally, ethanol inhibition of LTP in the hippocampus may underlie episodes of amnesia after alcohol binge drinking [108].

4.4.2 Acute Tolerance, Rebound Potentiation, and LTF

As stated above, prolonged ethanol exposure leads to the development of acute tolerance of NMDARs to ethanol, which is evidenced by a reduction of ethanol inhibition of receptor activity, which may eliminate the depressive effect of ethanol on the induction of NMDAR-dependent LTP. For example, Tokuda et al. observed in hippocampal slices that LTP was abolished by acute application of 60 mM ethanol, but LTP was inducible when ethanol was gradually increased to 60 mM over 75 minutes [109]. They speculated that this slow increase in ethanol concentration induced an acute tolerance of NMDAR activity to ethanol, which preserved NMDAR function and thus LTP induction.

The ability to induce LTP during acute ethanol tolerance further suggests that synaptic plasticity and memory formation may be developed in response to ethanol exposure. In addition, it is intriguing to speculate that the upregulation of NMDAR function in response to ethanol observed ex vivo may contribute to the aberrant learning and memory, as well as habit formation associated with alcohol addiction [110,111].

4.4.3 Chronic Ethanol Exposure and Withdrawal

Withdrawal from chronic exposure to ethanol leads to excessive activity of the NMDAR. For instance, withdrawal of ethanol following chronic exposure increased the firing rate of hippocampal neurons in both cultures [75] and slices [81]. This effect was abolished by the NMDR agonist APV. In addition, the excessive activity of the NMDAR upon chronic exposure to ethanol, in conjunction with withdrawal and the increase in Ca2+ influx, is believed to be the major cause of neurotoxicity and neuronal cell death [112], which were detected mainly in NMDAR-containing neurons such as cortical pyramidal cells, hippocampal CA1 pyramidal cells, granule cells in the dentate gyrus, and amygdala neurons [113,114].

Inhibition of NMDARs with an NR2B subunit antagonist was shown to block the neurotoxic actions of ethanol in cultured cortical neurons [115]. The NMDAR-mediated neurotoxicity and cell death resulting from ethanol withdrawal may account for the decrease in the number of neurons in the cortex [116] and in the cerebellum [117], and a decrease in the number of cortical neuronal dendrites [118], and dentate gyrus granule cells [119,120]. Hyperactivation of the NMDAR may be the cause of seizures and other symptoms observed in rodents and humans upon ethanol withdrawal, which, if not treated, could be fatal [121,122].

4.5 NMDA RECEPTORS AND BEHAVIORS ASSOCIATED WITH ETHANOL EXPOSURE

The NMDAR has been linked to many behavioral paradigms associated with ethanol exposure such as intoxication, reward, sensitization, and relapse [6,123]. Below is a summary of some of the studies linking the NMDAR to ethanol-associated behavioral paradigms in vivo.

4.5.1 Ethanol Intoxication

Ethanol intoxication is measured in rodents by the length of sleep time upon systemic injection of hypnotic doses (3–4 g/kg) of ethanol. Miyakawa et al. showed that Fyn deletion mice were more sensitive to intoxicating doses of ethanol and therefore their sleep time was longer than the Fyn+/− mice [63]. We found that systemic administration of the NR2B-specific inhibitor, ifenprodil, together with ethanol increased the length of sleep time of the Fyn+/+ mice to the same level as the Fyn−/− mice [124]. Taken together, these results suggest that Fyn-mediated phosphorylation of NR2B subunits and the development of acute tolerance reduce the in vivo sensitivity to hypnotic doses of ethanol.

Support for a potential role of NR2B-containing NMDARs in the attenuation of the level of intoxication was reported in a recent study in which systemic inhibition of NR2B-containing NMDARs with CGP-37848 or Ro-25-6981 significantly increased sleep time in C57BL/6J mice [125]. These results are also in line with numerous studies by Kalant and colleagues showing that the NMDAR antagonists (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol exposure in vivo [126–128].

4.5.2 Sensitization

Sensitization is defined as a progressive increase in the effect of the same dose of a drug when administered repeatedly over time. Sensitization to ethanol’s actions is measured in rodents by an increase in the acute stimulating effects of systemic administration of a nonintoxicating dose of ethanol on locomotion. The link between the NMDAR and sensitization stemmed from studies showing that the noncompetitive NMDAR antagonist MK-801 reduced the stimulant effects of ethanol and prevented expression of sensitization [129,130]. However, Meyer and Philips reported that repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol’s locomotor stimulant effect [131]. Interestingly, Broadbent et al. reported that the NR2B-containing NMDAR-specific antagonist, ifenprodil, did not alter expression of sensitization, suggesting the involvement of non–NR2B-containing receptors [130]; this possibility needs to be confirmed in future studies.

4.5.3 Reward

The level of ethanol reward is measured in mice in a conditioned place preference (CPP) paradigm. Pretreatment with the competitive NMDAR antagonist CGP-37849 reduced the acquisition of ethanol-induced CPP, possibly by impairing the ability of mice to learn the task [132]. Kotlinska et al. found that a noncompetitive NMDAR antagonist neramexane inhibited the acquisition and expression of ethanol-induced CPP [133]. In addition, Biala et al. observed that coapplication of the noncompetitive NMDAR antagonist dizocilpine and the NMDAR antagonist L-701,324 acting on the glycine binding site prevented the acquisition of ethanol-induced CPP [134]. Interestingly, the NR2A−/− and heterozygous mice did not exhibit ethanol-induced CPP, whereas their WT littermates did, suggesting that NR2A-containing NMDARs are important for the rewarding actions of ethanol [135]. Interestingly, we found that Fyn kinase is not required for ethanol-induced CPP [124], suggesting that the NR2A- and not NR2B-containing NMDAR is required for the rewarding properties of ethanol.

4.5.4 Relapse

Alcohol drinking after a period of abstinence can be mimicked in rodents by an alcohol deprivation paradigm in which access of ethanol is renewed after a period of abstinence. This leads to a significant increase in ethanol self-administration. Hotler et al. reported that repeated administration of NMDAR antagonists dose-dependently decreased ethanol consumption in an ethanol deprivation model [136], suggesting that NMDAR inhibitors could be developed as medications to prevent relapse to alcohol drinking.

4.5.5 Ethanol Withdrawal Syndrome

As mentioned above, ethanol withdrawal syndrome is a life-threatening condition and is also a hallmark for physical dependence to ethanol [122]. Other symptoms of ethanol withdrawal syndromes in humans include tachycardia, sweating, tremor, hypertension, anxiety, agitation, auditory and visual hallucinations, and confusion [121,122]. Therefore, ethanol withdrawal symptoms are disabling enough to lead many subjects to resume alcohol consumption at the early stages of withdrawal [2,112,137,138].

4.6 MODULATORS OF NMDA RECEPTOR FUNCTION AND TREATMENT OF ALCOHOL ABUSE AND DEPENDENCE

During the past 20 years, NMDAR antagonists have been assessed for their potential use as medication for the treatment of various CNS related disorders such as stroke, pain, and Alzheimer’s disease [139,140]. Several NMDAR antagonists have been tested in human trials as potential drugs that alleviate adverse phenotypes that are associated with alcoholics. For example, administration of the NMDAR antagonist, ketamine, to recovering alcoholics reduced psychosis, negative symptoms, dysphoric mood, and worsening of cognitive function [141]. A recent study showed that the well-tolerated NMDAR antagonist memantine [142] reduced alcohol-induced cue-induced craving [143], suggesting that well-tolerated NMDAR antagonists such as memantine could potentially be used as medications for the treatment of alcohol addiction.

Finally, the anticraving and relapse drug, acamprosate, was shown to modulate the activity of the NMDAR, suggesting that the beneficial actions of the drug may be due, at least in part, to its action on the channel. In 2004 the FDA approved acamprosate (Campral) as an anticraving and relapse medication after clinical trials showed efficacy of the drug in maintaining abstinence in recovering alcoholics (FDA 2004-07-29). Interestingly, various studies suggested that acamprosate modulates the activity of the NMDAR. Acamprosate was shown to act as a weak antagonist [144] or a partial “coagonist” at the NMDAR, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation [145]. Acamprosate was also shown to decrease NMDAR activity in cortical neurons [146]. However, in neurons of the hippocampal CA1 region and of the nucleus accumbens, the compound enhanced NMDAR function [147,148]. In primary cultured striatal and cerebellar granule cells, acamprosate exposure did not result in alteration of NMDA-induced currents [149], nor did it alter the inhibitory effects of ethanol (10–100 mM) on receptor function [149]. However, acamprosate was found to cause an up-regulation of the NR1 subunit in the cortex and hippocampus [144]. These data suggest that the actions of acamprosate on the NMDAR are complex and should be further explored.

ACKNOWLEDGMENT

This work was supported by NIAAA (R01/AA/MH13438-O1A1) (D.R.).

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