Glutamate-mediated transmission, alcohol, and alcoholism

Neurochemistry International 37 (2000) 509±533

www.elsevier.com/locate/neuint

Review

Glutamate-mediated transmission, alcohol, and alcoholism Peter R. Dodd*, Alison M. Beckmann, Marks S. Davidson, Peter A. Wilce Department of Biochemistry, University of Queensland, Brisbane, Qld 4072, Australia

Abstract Glutamate-mediated neurotransmission may be involved in the range of adaptive changes in brain which occur after ethanol administration in laboratory animals, and in chronic alcoholism in human cases. Excitatory amino acid transmission is modulated by a complex system of receptors and other e€ectors, the ecacy of which can be profoundly a€ected by altered gene or protein expression. Local variations in receptor composition may underlie intrinsic regional variations in susceptibility to pathological change. Equally, ethanol use and abuse may bring about alterations in receptor subunit expression as the essence of the adaptive response. Such considerations may underlie the regional localization characteristic of the pathogenesis of alcoholic brain damage, or they may form part of the homeostatic change that constitutes the neural substrate for alcohol dependence. 7 2000 Elsevier Science Ltd. All rights reserved. Keywords: Ethanol; Pathogenesis; Dependency; Excitatory amino acid; Receptors-subunits; Treatment of dependency; Drug mechanisms; Review

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

2.

E€ects of ethanol on neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

3.

Glutamate-mediated transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511

4.

NMDA receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

5.

Modulatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Glycine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Channel blockers Ð the MK801/phencyclidine (PCP) site 5.3. Mg2+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Polyamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.

Other modulatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 6.1. Zn2+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 6.2. Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

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Abbreviations: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionate; GABA, g-aminobutyrate; KA, kainate; MK801, (+)-5-methyl10,11-dihydro-5H-dibenzo[a,d ]cyclohept-5,10-imine maleate (dizocilpine); NMDA, N-methyl-D-aspartate; PCP, phencyclidine; TCP, thienylcyclohexylpiperidine. * Corresponding author. Fax: +61-7-3365-4699. E-mail address: [email protected] (P.R. Dodd). 0197-0186/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 9 7 - 0 1 8 6 ( 0 0 ) 0 0 0 6 1 - 9

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P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

6.3. 6.4. 6.5.

Pregnenolone sulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516 Redox modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516 Protons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

7.

AMPA/KA receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

8.

Metabotropic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

9.

Ethanol and glutamate Ð NMDA sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

10.

Acute e€ects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

11.

Recombinant studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518

12.

Chronic e€ects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519

13.

Adaptive changes in subunit combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520

14.

The glycine co-agonist site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521

15.

Other 15.1. 15.2. 15.3.

modulatory sites Redox . . . . . . . Mg2+ . . . . . . . . Polyamines . . . .

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521 521 521 522

16.

Ethanol and NMDA-induced excitotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522

17.

Non-NMDA receptors and ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523

18.

Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524

19.

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524

1. Introduction While ethanol is one of the human race's oldest drugs, knowledge of its mechanism of action is incomplete. The primary brain lesions and adaptive changes in neuronal function associated with chronic consumption may have complex origins. Ethanol may damage the nervous system directly (McMullen et al., 1984; King et al., 1988); via its oxidative metabolite acetaldehyde (Bondy and Guo, 1995; Hunt, 1996); or through non-oxidative metabolites such as fatty acid ethyl esters (Laposata and Lange, 1986; Bora and Lange, 1993; de Jersey and Treloar, 1994) or phosphatidylethanol (Gustavsson, 1995). Malnutrition, vitamin de®ciencies (especially of thiamin) and alcoholic liver disease complicate the cerebral e€ects of chronic alcoholism (Thomson et al., 1983; Victor et al., 1989). These factors are all interrelated in the pathogenesis of ethanol-induced brain damage (Butterworth, 1995).

Neuroactive drugs such as ethanol in¯uence neurotransmission to alter mood. Alcohol is also a drug of abuse, where long-term use can lead to addiction, the compulsion to take the drug and loss of control over intake (Koob, 1996), or dependence, the need for continued drug exposure to avoid withdrawal (Nestler et al., 1993). Tolerance, where a reduced e€ect follows repeated exposure to a constant dose, or an increased dose is needed to maintain the same e€ect, is also common (Nestler, 1992; Nestler et al., 1993; Snell et al., 1996b). The phenomena of tolerance and withdrawal have shaped hypotheses concerning the mechanism of drug dependence. The initial e€ect of a drug may be counteracted by homeostatic changes in systems that mediate the primary e€ect of the drug. With continued drug use these changes become more pronounced, such that the brain is only returned to near-normal function in the presence of the drug.

P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

When the drug is removed, these neuroadaptations are unmasked and lead to the elaboration of the withdrawal syndrome. Thus, long-lasting plastic changes in brain function have been hypothesized to underlie drug dependence (Nestler et al., 1993). Substantial evidence suggests that this plasticity is mediated, at least in part, by altered gene expression (Nestler, 1994). Together these proposals form a theory of physical dependence. The signs of ethanol withdrawal are, for the most part, opposite to those of chronic intoxication (Ho€man and Tabako€, 1994). In human alcoholics, ethanol withdrawal is characterized by tremulousness, convulsions Ð which have many characteristics in common with grand mal seizures (Ho€man et al., 1992) Ð and hallucinations, typically occurring 6±48 h after the last drink. Delerium tremens is a more serious syndrome, which involves profound confusion, hallucinations, and severe autonomic instability. It typically begins 48±96 h after drinking has ceased (Victor, 1983). Ethanol withdrawal is also characterized by an increased craving for alcohol, or drug-seeking behaviour. These symptoms can be seen as physiological and psychological, and they may arise from di€erent neural substrates (Koob et al., 1992; Samson and Harris, 1992). Ethanol withdrawal unmasks the homeostatic changes that have produced both physical and psychological dependence, and constitutes a transitional stage in which the brain moves to the ethanol-free state. The latter may involve a return to pre-drug functioning, but may also have long-term consequences such as kindling or neuronal death (Ho€man and Tabako€, 1994). All of these changes may involve altered protein and/or gene expression (Matsumoto et al., 1993b; Ortiz et al., 1995). Altered membrane ¯uidity has been proposed to underlie ethanol's actions in the brain. Ethanol at high doses in vitro increases synaptic membrane ¯uidity, consistent with an anaesthetic e€ect (Chin and Goldstein, 1977b). The increased ¯uidity has been correlated with both the development of tolerance (Chin and Goldstein, 1977a) and the susceptibility to intoxication (Goldstein et al., 1982). It may be due to changes in the composition of membrane lipids (Zheng et al., 1996) and may lead to disrupted functions in membrane-associated proteins (Goldstein and Chin, 1981). However, the e€ects of ethanol (and other anaesthetics) at the GABAA receptor (see below) do not appear to be due to altered membrane ¯uidity (Huidobro-Toro et al., 1987). Ethanol does not appear to act at an intra-membrane site on chimeric serotonin 5HT3/acetylcholine nACha7 receptors; rather, inhibition of this channel occurs via an action in the extracellular (nACha7) portion (Yu et al., 1996).

511

2. E€ects of ethanol on neurotransmission Recent studies have demonstrated that ethanol exerts speci®c actions at a number of neurotransmitter receptors, even though it is a relatively non-speci®c drug (Lovinger, 1997). It is doubtful whether an ``ethanol receptor'' will be found (Merikangas, 1990). Rather, ethanol may disrupt receptor or e€ector proteins by direct interaction; at high concentrations, it may change the composition of lipids in the surrounding membrane (Nutt and Peters, 1994; Tan and Weaver, 1997). Ethanol has e€ects on virtually every neurotransmitter system (reviewed in Deitrich et al., 1989; Wilce et al., 1991; Nevo and Hamon, 1995; Phillips and Shen, 1996; Tabako€ et al., 1996). These e€ects may contribute to many of the physiological or psychological symptoms associated with ethanol use and withdrawal. Two of the best-characterized systems are those for the excitatory and inhibitory amino acids, glutamate and g-aminobutyrate (GABA). Alterations in these systems may underlie the hyperexcitability observed during ethanol withdrawal (Lovinger, 1993b; Crews et al., 1998), and may also play a roÃle in alcohol dependency (Tsai et al., 1995; Koob et al., 1998): acamprosate, which appears ecacious in maintaining abstinence in the treatment of alcohol dependency (Besson et al., 1998), interacts selectively with glutamate- and possible GABA-mediated neurotransmission (Berton et al., 1998). This review will focus on the interactions between ethanol, both in acute experimental paradigms and as the central factor in chronic alcoholism and its animal models, and glutamate-mediated neurotransmission. As discussed elsewhere in this issue (Loh and Ball, 2000; Reilly and Buck, 2000), sensitivity to alcohol and alcoholism may be genetically inherent in both animals and human subjects, and emerging studies suggest that genes associated with amino acid neurotransmission may indeed be linked to such sensitivity (Kirschner et al., 1994; Buck et al., 1997; Buckman and Meshul, 1997); these aspects will not be considered further here. 3. Glutamate-mediated transmission Glutamate is the neurotransmitter at the majority of excitatory synapses in the mammalian CNS. Two broad subclasses of glutamate receptors exist: ionotropic receptors, which are ligand-gated ion channels; and metabotropic receptors, which are coupled to secondmessenger pathways through G proteins (reviewed in Nakanishi, 1992; Schoepfer et al., 1994). The ionotropic receptors are further subdivided (Collingridge and Lester, 1989) on the basis of their sensitivity to the exogenous agonists N-methyl-D-aspartate (NMDA receptors), DL-a-amino-3-hydroxy-5-methylisoxazole-4-

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propionate (AMPA receptors) and kainate (KA receptors). The NMDA receptors are assembled from NR1 and NR2 subunits, while the non-NMDA receptors comprise GluR1±7 and KA1±2 subunit types (Nakanishi, 1992). Numerous heteromeric receptors can be formed, which can have distinctive properties with respect to ligand gating, modulation, and function. 4. NMDA receptors The NMDA receptor channel has slower kinetics than AMPA/KA receptors and mediates Na+ and Ca2+ in¯ux. The slow kinetics of channel opening allows both summation of glutamate responses and a large in¯ux of calcium into the cell. This increase in intracellular calcium concentration is believed to be critical for many of the proposed roÃles of the NMDA receptor (see below). Ion ¯ux through the NMDA receptor is voltage-dependent. When the cell is at resting potential, Mg2+ binds within the ion channel and blocks the cation ¯ux. It is likely that synapticallyreleased glutamate ®rst activates AMPA/KA receptors, thereby causing depolarization of the post-synaptic cell and release of the Mg2+ ion such that other cations can move through the NMDA receptor ion channel (Nowak et al., 1984; Westbrook and Mayer, 1987). The NMDA receptor complex exhibits ®ve main domains: (1) a glutamate recognition site where the agonist NMDA also binds; (2) a Mg2+ binding site within the channel pore; (3) a binding site for (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d ]cyclohept-5,10imine maleate (MK801; dizocilpine) and dissociative anaesthetics (phencyclidine, ketamine) within the channel pore that interacts with the cation binding site and has a requirement for agonist binding to open the channel for ligand access; (4) a glycine-binding co-agonist site that modulates the agonist recognition site; and (5) a polyamine modulatory site (Wong et al., 1986; Kleckner and Dingledine, 1988; Farooqui and Horrocks, 1991; Barnes and Henley, 1992; Scott et al., 1993; Barnard, 1997). There are also sites which bind Zn2+, protons, and redox reagents (Peters et al., 1987). NMDA receptors are heavily glycosylated multi-subunit complexes (Moriyoshi et al., 1991; Brose et al., 1993). Early sequence analysis suggested four transmembrane segments (M1±M4) within each subunit typical of transmitter-gated ion channels; the subunit sequences have homology with each other and with subunits of AMPA and KA receptors (Moriyoshi et al., 1991). More recently, the model was revised to accommodate a transmembrane segment 2 that does not cross the membrane but rather forms a kink within the membrane analogous to the pore-forming domain of the voltage-activated K+ channels. Inclusion of this P-

element domain in the model predicts that the COOH terminal of the subunit protein is intracellular and potentially subject to post-translational modi®cation (Dani and Mayer, 1995). An NR1 subunit …z1 in the mouse: Moriyoshi et al., 1991; Yamazaki et al., 1992) is absolutely required, since mutants lacking this allele die as neonates even though their overall neuroanatomy appears normal (Forrest et al., 1994; Li et al., 1994). The subunit contains 920 amino acids, giving a molecular weight of 103,477 Da (Moriyoshi et al., 1991). There are ten consensus glycosylation sites (Moriyoshi et al., 1991): Brose et al. (1993) used biochemical techniques to demonstrate heavy glycosylation of NR1. Homomeric NR1 receptors expressed in Xenopus ooÈcytes are functional, but highly active receptors are only produced by co-expression of NR1 and NR2 subunits (Kutsuwada et al., 1992; Monyer et al., 1992). Incorporation of the NR2A±D (mouse e1±4 respectively) subunits reconstitute many properties of native NMDA receptors (Ikeda et al., 1992; Kutsuwada et al., 1992; Meguro et al., 1992; Monyer et al., 1992; Ishii et al., 1993). The NR2A±D subunits range in size from 133 to 163 kDa (Meguro et al., 1992; Monyer et al., 1992). Homomeric expression of NR1 subunit cDNA does not generate glutamate-gated ion channels in mammalian cells (Grimwood et al., 1995). Major determinants of glutamate binding reside in the extracellular domain of the NR2 subunits (Laube et al., 1997), consistent with the low eciency and unusual properties of glutamate binding to homomeric NR1 subunits (Durand et al., 1992; Hollmann, 1997). Other potential subunits have been identi®ed, including the glutamate-binding protein (Kumar et al., 1991) and NR±L (Ciabarra et al., 1995; Sucher et al., 1995). The synaptic membrane NR1 protein has been shown to be part of a receptor complex with a molecular mass of 730 kDa (Brose et al., 1993). The total number of subunits in native NMDA receptors is not known, but may be ®ve, as occurs in nicotinic receptors (Ferrer-Montiel and Montal, 1996), or four, as in ion channels with pore loops (MacKinnon, 1995). Natively expressed NMDA receptors are likely to include at least one member of the NR2 class. Immunoprecipitation studies under non-denaturing conditions suggest that at least a sub-population of native receptors contains two di€erent NR2 subunits (Wafford et al., 1993; Chazot et al., 1994; Sheng et al., 1994; Ebralidze et al., 1996). Using more selective and quantitative antibodies, Luo et al. (1997) concluded that the form of NMDA receptor with highest abundance in adult rat cerebral cortex contains all three (NR1, NR2A, NR2B) subunits in a single ternary structure, with binary species (NR1/NR2A and NR1/ NR2B) being present at much lower levels. In contrast, the co-association of NR1, NR2A and NR2B subunits in the same receptor was shown directly, and the triple

P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

combination was identi®ed as a minor sub-population, compared with binary NR1/NR2A, NR1/NR2B and homomeric NR1 receptors (Chazot and Stephenson, 1997). Radioligand binding studies in rat forebrain delineated four distinct populations of heteromeric NMDA receptors (Monaghan et al., 1997). Agonistpreferring receptors, de®ned by L-[3H]glutamate binding that is weakly inhibited by D-AP5, were found predominantly in brain regions that contained both NR2B and NR1 mRNA moieties (Buller et al., 1994). The distribution of antagonist-preferring NMDA receptors, de®ned by 3-[3H](carboxypiperazine-4-yl)propyl-1-phosphonate binding, was virtually identical to that of NR2A subunits, while cerebellar NMDA receptors with a distinctive pharmacological pro®le corresponded anatomically to the distribution of the NR2C subunit (Buller et al., 1994; Monaghan et al., 1997): co-expression of NR2C and NR1 mRNA in ooÈcytes yields receptors pharmacologically similar to native cerebellar receptors. A pharmacologically distinct NMDA receptor was identi®ed in the midline thalamus (Monaghan et al., 1997); its anatomical distribution was virtually identical to that of the NR2D subunit (Buller et al., 1994). Diversity of subunit composition results in considerable heterogeneity of biological responses. The binding parameters and/or activity of agonists, antagonists and modulators are all subject to subunit-speci®c variation (reviewed in Mori and Mishina, 1995). The diversity is further ampli®ed by eight splice variants of the NR1 subunit (Anantharam et al., 1992; Durand et al., 1992; Nakanishi et al., 1992; Sugihara et al., 1992; Yamazaki et al., 1992; Hollmann et al., 1993). There are three splice ``cassettes'' in the NR1 coding sequence. One is located at the 5 ' end of the mRNA (which encodes the putative extracellular domain); inclusion results in a 21-amino-acid insert in the protein. The other two cassettes are located at the 3 ' end, which encodes the intracellular C-terminus. They may be spliced out independently or together, leading to the generation of alternative carboxy termini (Sugihara et al., 1992; Hollmann et al., 1993). The NR2C (Suchanek et al., 1995) and NR2D (Ishii et al., 1993) receptor subunits also exist as two alternatively spliced variants. The type of NR2 subunit present a€ects the ecacy of modulatory agents (Durand et al., 1992; Hollmann et al., 1993; Williams et al., 1994). NMDA receptors are distributed throughout the brain (Nakanishi, 1992). The anatomical organization of NR2 subunits is highly heterogeneous in rat forebrain, which would result in regionally functional diversity of the receptor (Watanabe et al., 1993). In contrast, in situ hybridization histochemical and immunocytochemical studies have demonstrated that NR1 is present in most neurones in all regions of the

513

brain (Moriyoshi et al., 1991; Petralia et al., 1994). The most densely stained cells include pyramidal and hilar neurones of the CA3 region of the hippocampus (Petralia et al., 1994). In situ hybridization histochemistry with splice-speci®c NR1 probes has shown striking regional di€erences in the pattern of expression. No two patterns are identical and there is considerable overlap, which suggest that each of the eight splice variants is expressed (Laurie et al., 1995). There is no pattern of expression common to NR1 splice variants and NR2 subunits (Blahos and Wenthold, 1996), though complexes containing both NR2A and NR2B subunits are rare. Most complexes may contain only a single NR2 subunit, but at least two di€erent NR1 splice variants (Blahos and Wenthold, 1996). NMDA receptor activation allows the in¯ux of Ca2+ from the extracellular milieu. This raises the intracellular concentration of Ca2+ ions (MacDermott et al., 1986), principally in the apical dendrites in the vicinity of the a€erent synaptic input (Regehr and Tank, 1990). This in turn may promote activation of protein kinase C by its translocation from the cytosol to the cell membrane (Wolf et al., 1985), or activation of other Ca2+-dependent signalling pathways including Ca2+/calmodulin-dependent kinase, tyrosine kinase, protein phosphatases, proteases and phospholipases such as phospholipase A2 (Lerea et al., 1995; see Lerea and McNamara, 1993 for review). Activation of phospholipase A2 and subsequent prostaglandin production may then stimulate protein kinase A and bring about an increase in cyclic AMP levels (Partington et al., 1980; Lerea and McNamara, 1993). 5. Modulatory agents 5.1. Glycine The NMDA receptor is unique in its requirement for the co-agonists glutamate and glycine for complete activation of the channel (Kleckner and Dingledine, 1988). The integral strychnine-insensitive glycine-binding site must be stimulated for the associated cation channel of the receptor to be activated (Johnson and Ascher, 1987; Kleckner and Dingledine, 1988). The allosteric linkage between the glutamate- and glycinebinding sites is indicated by enhanced agonist-stimulated binding of [3H]MK801 or [3H]thienylcyclohexylpiperidine (TCP) in adult rat brain homogenates in the presence of glycine (Reynolds et al., 1987). Autoradiography studies have demonstrated a similar anatomical distribution of strychnine-insensitive glycineand NMDA-sensitive glutamate-binding sites (Cotman et al., 1987). Measurements of glycine concentrations in extracellular and cerebrospinal ¯uid indicate that these are theoretically sucient to saturate the glycine

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site in vivo (Kemp and Leeson, 1993). This may not be so, however, since the administration of glycine agonists positively modulates NMDA receptormediated increases in cyclic GMP and potentiates the seizure-inducing potency of NMDA agonists (Wood et al., 1989; Singh et al., 1990a). Glycine-site antagonists have been found to be anticonvulsants and to have neuroprotective properties (Priestley et al., 1990; Singh et al., 1990a). NR2 subunits expressed alone do not produce channels gated by glutamate and glycine (Moriyoshi et al., 1991; Meguro et al., 1992; Ishii et al., 1993). Homomeric NR1 assembly in transfected cells reveals a highanity radioligand glycine binding site, suggesting that this agonist-binding domain at least is located on the NR1 subunit, with the NR2 subunit playing a modulating roÃle (Lynch et al., 1994). Site-directed mutagenesis of D481 and K483 in NR1 resulted in a 160-fold lower anity for glycine, implicating an interaction between the carbonyl group of the aspartate residue and the amino group of glycine (Wa€ord et al., 1995). Mutation of D732 in the extracellular loop decreased sensitivity to glycine by more than 4000-fold without altering the sensitivity to glutamate (Williams et al., 1996). As glycine-site antagonists did not reduce sensitivity in these mutants, D732 may not be directly involved in the binding of glycine, but may be involved in the coupling of glycine binding to channel opening (Williams et al., 1996). 5.2. Channel blockers Ð the MK801/phencyclidine (PCP) site [3H]TCP and [3H]MK801 have been extensively used for labeling NMDA receptors. MK801 is one of the most potent and selective NMDA antagonists, with an in vitro anity in the 1±10 nM range and a high ratio of speci®c to non-speci®c binding (Reynolds and Palmer, 1991). The binding of these PCP-like ligands is both use- and voltage-dependent; thus, for them to e€ectively block the receptor it must ®rst be activated (Huettner and Bean, 1988). These ®ndings suggest that PCP-like ligands bind to sites located within the ion channel (Reynolds and Palmer, 1991). Binding of [3H]MK801 to well-washed membrane preparations is enhanced by glutamate, glycine and polyamines, and inhibited by antagonists at these sites (Foster and Wong, 1987; MacDonald and Nowak, 1990). Quantitative receptor autoradiography using [3H]MK801 has revealed a heterogeneous distribution, with the hippocampus containing the highest concentration of binding sites (Bowery et al., 1988). NMDA receptors labeled by [3H]MK801 are qualitatively similar in their sensitivity to a range of NMDA receptor modulators in all brain regions. However, quantitative di€erences are apparent. The most striking of these in laboratory

animals is that the eciency with which agonists increase binding is lower in hindbrain regions (cerebellum) than in cortex, striatum and hippocampus (Reynolds and Palmer, 1991). Within human cerebral cortex, we found marked regional di€erences in the pro®les of the spermine- and glutamate-incremented enhancement of speci®c [3H]MK801 binding (Mortensen and Dodd, 1999). Radiolabeled forms of channel blockers have an advantage over radioligands such as [3H]glutamate in that they provide information on the association and dissociation rates. Agents that bind to the dissociative site are valuable biochemical tools for probing the interactions of drugs with the NMDA receptor. 5.3. Mg2+ NMDA receptors show voltage-sensitive blockade by magnesium ions which is alleviated by depolarizing potentials (Nowak et al., 1984). This gives the NMDA receptor its most distinctive physiological feature, namely the increase in inward Ca2+ current as the surrounding membrane becomes depolarized (Foster and Fagg, 1987). The site of action of Mg2+ is independent of that of PCP-like ligands, as it enhances the dissociation of [3H]MK801 binding (Reynolds and Miller, 1988). Prior to recombinant studies, it was concluded from biophysical measurements that the site of voltage-dependent Mg2+ block lies within the ion-permeable pore (Ascher and Nowak, 1987; Hollmann, 1997). Expression studies identi®ed the site of Mg2+ block as an asparagine residue (Asn616) in the putative transmembrane domain 2 (Hollmann, 1997). NR2A and NR2B form channels more sensitive to Mg2+ than do NR2C and NR2D-containing complexes (Monyer et al., 1994). The use of chimeric constructs of NR2B/NR2C has allowed three small segments (M1, M2±3 linker, M4) that determine the sensitivity to Mg2+ block to be identi®ed (Kuner and Schoepfer, 1996). The injection of MgSO4 simultaneously with an i.c.v.-administered NMDA agonist results in complete neurotoxic and behavioural protection (Wolf et al., 1990). NMDA does not cause neurotoxicity in cultured neurones when Mg2+ is allowed (under non-depolarizing conditions) to block the channel (Frandsen and Schousboe, 1994). Absence of Mg2+ from the incubation medium results in both an increased NMDAinduced intracellular Ca2+ ion concentration and neurotoxicity (Frandsen and Schousboe, 1994). 5.4. Polyamines The polyamines spermine and spermidine increase the anity of NMDA receptor for [3H]MK801 (Ransom and Stec, 1988). They generate biphasic concen-

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tration curves, enhancing [3H]MK801 binding at low concentrations and decreasing it at higher concentrations (Williams et al., 1989). The stimulatory e€ect of polyamines is due to an increase in the association rate of [3H]MK801, while their inhibitory e€ect is due to a decrease in equilibrium binding. This suggests that polyamines have more than one site of action on the NMDA receptor complex (Marvizon and Baudry, 1994). Electrophysiological experiments have also shown that spermidine and spermine have multiple e€ects on NMDA receptor currents. At low concentrations spermine enhances NMDA receptor whole-cell current by increasing channel opening frequency, while at high concentrations its enhancement is reduced by a voltage-dependent reduction in single-channel conductance and average duration of opening (Rock and Macdonald, 1992a,1992b). The potentiation by spermine, however, varies widely (0±200%) between individual neurones, suggesting a di€erential sensitivity to polyamines (Rock and Macdonald, 1992a, 1992b; Benveniste and Mayer, 1993). At above-maximal concentrations of glutamate and glycine, spermidine and spermine act elsewhere than on amino acid binding sites (Williams et al., 1989). Saturable, low-anity and high-density [3H]spermidine sites are found throughout the rat brain (Ogita and Yoneda, 1990). There is a clear correlation between the abilities of several polyamines to displace [3H]spermidine binding and their potentiation of [3H]MK801 binding (Yoneda and Ogita, 1994). Both spermidine and spermine exhibit marked regional variability in their ability to enhance the binding of [3H]MK801 in washed rat brain sections (Subramaniam and McGonigle, 1991), as well as in di€erent human cerebrocortical regions (Mortensen and Dodd, 1999). The presence of a propylene±diamine moiety [NH2-(CH2)3-NH-] in a synthetic polyamine gives it agonist or partial-agonist activity at the polyamine site on the NMDA receptor complex (Williams et al., 1989, 1991). Based on their ability to decrease [3H]MK801 binding, diethylenetriamine, 1,10-diaminodecane, arcaine, ifenprodil and the conanotkin group of marine peptides have been proposed as antagonists or inverse agonists of the stimulatory action of polyamines on the NMDA receptor (Carter et al., 1989; Reynolds et al., 1990; Williams et al., 1990; Nielsen et al., 1999). Polyamines increase the anity of glycine for its recognition site by interacting with an arcainesensitive site on the NMDA receptor complex (Reynolds and Rothermund, 1995). The anti-craving drug acamprosate (calcium N-acetylhomotaurine) acts at a speci®c site which appears to interact allosterically with the polyamine site (Naassila et al., 1998). Heterogeneity in the properties of the NMDA receptor and its interaction with the amino acid sites suggests there are probably di€erences in subunit composition in di€erent brain regions (Mortensen and Dodd, 1999).

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It is now recognised that polyamines have multiple e€ects on the NMDA receptor. These include: (a) glycine-independent stimulation, which involves an increase in NMDA-induced whole-cell currents in the presence of saturating concentrations of glycine; (b) voltage-dependent inhibition (more pronounced at hyperpolarized potentials), brought on by open-channel block or screening of surface charge on the receptor; (c) glycine-dependent stimulation, in which spermine increases the anity of the receptor for glycine; (d) a decrease in agonist anity, as the stimulatory e€ect of spermine at NR1A/NR2B receptors is dependent on the concentration of NMDA or glutamate used to activate the receptor (Rock and Macdonald, 1992a, 1992b; Benveniste and Mayer, 1993; Williams, 1994b, 1997; Williams et al., 1994, 1995). Co-expression of NR1A (no amino terminal insert) with particular NR2 subunits in Xenopus ooÈcytes can markedly alter properties associated with the NR1 subunit. Inclusion of the NR1A variant is necessary for polyamine stimulation, but manifestation of this e€ect is controlled by the type of NR2 subunit in the heteromeric complex (Williams et al., 1994; Zhang et al., 1994). Glycine-independent stimulation by spermine occurs in homomeric NR1A but not homomeric NR1B receptors, heteromeric NR1A/NR2B but not NR1A/ NR2A or NR1A/NR2C receptors, and not in heteromeric complexes containing NR1B subunits (Williams, 1994b). Glycine-dependent stimulation is seen with NR1A/NR2A and NR1A/NR2B receptors, while voltage-dependent spermine inhibition occurs with similar magnitude in NR1A/NR2A or NR1A/NR2B receptors but is absent in NR1A/NR2C receptors (Williams, 1994b). There is evidence that glycine-independent and glycine-dependent stimulation by spermine involve two separate polyamine binding sites; the voltage-dependent block may involve a third polyamine binding site located near or in the ion channel pore (Benveniste and Mayer, 1993; Williams et al., 1995). Endogenous spermine (3 mM) potentiates the responses of functional NMDA receptors with a Hill coecient of 1.7, which also suggests the presence of multiple binding sites (Lerma, 1992). 6. Other modulatory agents 6.1. Zn2+ Zinc has non-competitive, voltage-insensitive antagonistic properties at the NMDA receptor ion channel, and is neuroprotective (Peters et al., 1987; Westbrook and Mayer, 1987). There is little interaction between zinc, glycine or Mg2+ binding (Westbrook and Mayer, 1987; Mayer et al., 1989). In the presence of glutamate, zinc is a potent inhibitor of [3H]MK801 binding (Rey-

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nolds and Miller, 1988). Zinc also dose-dependently inhibits [3H]glycine binding, suggesting that it may inhibit NMDA receptor function by non-competitively antagonizing the action of glycine (Yeh et al., 1990). In Xenopus ooÈcytes expressing NMDA receptors, Zn2+ inhibits of agonist-induced currents (Rassendren et al., 1990): the N-terminal domain may be involved in the Zn2+ binding site (Durand et al., 1992). Di€erential modulation of NR1/NR2A and NR1/NR2B currents by Zn2+ has been described, which suggests a modulatory roÃle for Zn2+ in regulating NMDA receptor channels (Chen et al., 1997a). 6.2. Histamine Histamine has been reported to potentiate NMDA receptor currents, possibly via the polyamine site (Bekkers, 1993; Vorobjev et al., 1993; Williams, 1994a). At micromolar concentrations it does not enhance NMDA currents in hippocampal slices, although it is active in cell-culture systems (Bekkers et al., 1996). There have been no reported e€ects of histamine on [3H]MK801 binding. 6.3. Pregnenolone sulfate Pregnenolone sulfate is an endogenous neuroactive steroid that has a non-genomic mechanism of action (Irwin et al., 1992). It inhibits both GABA- and glycine-induced Clÿ currents, and has been found to potentiate NMDA-induced currents and increases in intracellular Ca2+ ion concentration in the presence of saturating concentrations of NMDA and glycine (Wu et al., 1991; Irwin et al., 1992; Bowlby, 1993). Relatively small changes in the structure of pregnenolone sulfate cause changes in its activity at the NMDA receptor. This suggests there may be one or more steroid recognition sites associated with the channel complex (Irwin et al., 1994). It positively, directly and speci®cally modulated NMDA receptors in a mouse seizure model in vivo (Maione et al., 1992). As there is a steroid site on the GABA receptor, low concentrations of pregnenolone sulfate may have important neuromodulatory roÃles in mammalian CNS. 6.4. Redox modulators Strong oxidizing or reducing reagents, including endogenous glutathione, xanthine, and ascorbate, have been found to modulate the amplitude of NMDAmediated responses in a variety of neuronal preparations and recombinant systems. This may underlie important physiological and pathophysiological functions in the mammalian CNS (Aizenman et al., 1989; Leslie et al., 1992; Sullivan et al., 1994). The redox reagents react with critical sulfhydryls (cysteine residues)

on channel proteins. The disulphide bond Cys744± Cys798 is probably critical for receptor function (Sullivan et al., 1994; Gozlan and Ben-Ari, 1995). Reducing agents such as dithiothreitol enhance NMDA-gated currents while oxidizing agents such as 5-5 '-dithiobis(2-nitrobenzoic acid) decrease them (Sullivan et al., 1994). Mutation of NR1 cysteine residues abolishes dithiothreitol potentiation in NR1/NR2B recombinant complexes and abolishes spermine potentiation and proton inhibition (Sullivan et al., 1994). Dithiothreitol preferentially causes rapid potentiation in binary subunit con®gurations of NR1/NR2A subunits transfected into a mammalian cell line (Kohr et al., 1994). This e€ect is mimicked by the endogenous modulator glutathione. The NR2A subunit is important in the characteristic response to sulfhydryl redox reagents. Reduction by dithiothreitol resulted in an overall increase in [3H]MK801 binding but did not change the EC50 values for its potentiation by glutamate and glycine (Reynolds et al., 1990). 6.5. Protons The extracellular proton concentration is an important determinant of neuronal responses modulated by the NMDA receptor. Protons markedly suppress currents activated by NMDA in hippocampal and cerebellar neurones, while a decreased proton concentration potentiates them (Tang et al., 1990; Traynelis and Cull-Candy, 1990; Vyklicky et al., 1990). Protons negatively modulate [3H]MK801binding to the ion channel (Yoneda et al., 1994). The inhibition is not derived from interference with the interaction between endogenous agonists and their recognition domains (Yoneda et al., 1994). Acidic and alkaline transients associated with synaptic transmission are sucient to alter synaptic NMDA receptor activation, while acidi®cation of the interstitial spaces that occur during seizures or ischaemic shock will inhibit NMDA receptors, thereby providing feedback regulation (Traynelis and Cull-Candy, 1990; Chesler and Kaila, 1992). Recombinant studies in Xenopus have revealed that proton inhibition is determined by the presence of exon 5 in the NR1 subunit (Traynelis et al., 1995). These data raise the possibility that the predicted surface loop encoded by exon 5 acts as a tethered modulator of receptor function (Traynelis et al., 1995). 7. AMPA/KA receptors AMPA/KA receptors are involved in fast synaptic excitation in the brain and spinal cord (Salt, 1994). They were originally described pharmacologically as two separate sites on the basis of their di€erential sensitivity to the agonists AMPA and kainate. In general,

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AMPA produces a rapidly desensitizing response at AMPA receptors and kainate a weak, non-desensitizing response; the reverse is true at KA receptors (Lodge, 1997). Few selective AMPA receptor antagonists are available, and (e.g.) 2,3-dihydroxy-6-nitro-7sulfamoyl-benz(F)-quinoxaline only shows a 30-fold greater selectivity in displacing [3H]AMPA cf. [3H]kainate (Sheardown et al., 1990). The absence of potent and selective KA receptor antagonists has resulted in a dearth of knowledge of the synaptic function of these receptors, although the well-characterized excitotoxic e€ects of kainate suggest a strong link with Ca2+ entry pathways (Lodge, 1997). The distinction between AMPA and KA sites has become blurred following the cloning of multiple glutamate receptor subunits (e.g. Lerma et al., 1993). Molecular cloning has revealed four subunits, GluR1±4 (GluRA±D, respectively), with high anity for AMPA (Boulter et al., 1990; KeinaÈnen et al., 1990). Each shares sequence and structural homology with other ligand-gated ion channels and forms a functional AMPA receptor when homomerically expressed in a recombinant system. Each can be expressed in one of two splice variants (``¯ip'' or ``¯op'') by alternate expression of a 38-amino-acid exon at the N-terminal end which determines the susceptibility to receptor desensitization (Sommer et al., 1990). The subunits are di€erentially expressed; this confers speci®c properties on the receptor complex, including variations in the current-voltage relationship (Verdoorn et al., 1991) and the Na+/Ca2+ ¯ux (Hollmann et al., 1991). GluR2 is unique in showing low permeability to Ca2+, with crucial amino acid substitutions identifying a glutamine±arginine±asparagine site that controls Ca2+ and Mg2+ permeability of the ion channel (Lodge, 1997). Post-transcriptional site-speci®c alteration of mRNA (RNA editing) allows the cell to manipulate the ion pore and adjust Ca2+ permeability according to needs (Hollmann, 1997). Homomeric and heteromeric receptors lacking a GluR2 subunit show marked inward recti®cation and high permeability to Ca2+ (Verdoorn, 1997). Natively expressed neuronal receptors may contain the GluR2 subunit, as indicated by low AMPA-mediated Ca2+ permeability. The roÃle of GluR2 in pathological states has been little studied, although it has been shown that GluR2 mRNA expression falls relative to that of other AMPA subunits after kainate-induced seizures (Pollard et al., 1993). Genes encoding proteins with high anity for KA and some homology to AMPA subunit genes, designated GluR5±7 and KA1±2, have been cloned (Gregor et al., 1989; Wada et al., 1989; Bettler et al., 1990, 1992; Egebjerg et al., 1991; Werner et al., 1991; Herb et al., 1992). Of these, only GluR5 and GluR6 form functional KA-responsive channels when expressed homomerically in Xenopus ooÈcytes or mammalian cell

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systems. Functional heteromeric channels with selectivity for KA are formed from certain combinations (e.g. Herb et al., 1992), which suggests that these subunits may combine to give KA receptors with unique properties (Sommer and Seeburg, 1992). 8. Metabotropic receptors Seven subunits (mGlurR1±7) for a glutamate-activated G-protein-linked receptor family have been cloned and diverse splice variants identi®ed (Houamed et al., 1991; Masu et al., 1991; Abe et al., 1992; Pin et al., 1992; Tanabe et al., 1992; Minakami et al., 1993; Nakajima et al., 1993; Okamoto et al., 1994; Saugstad et al., 1994). Based on both sequence comparisons and the receptor-linked second-messenger systems activated, these receptors can be divided into three subclasses (reviewed in Pin and Duvoisin, 1995). Physiologically, the metabotropic glutamate receptors have been implicated in both excitatory and inhibitory neurotransmission through pre- and post-synaptic mechanisms; synaptic plasticity, including long-term potentiation; and both facilitation of, and protection from, excitotoxic neuronal death (Pin and Duvoisin, 1995). 9. Ethanol and glutamate Ð NMDA sites The NMDA receptor may mediate phenomena which include long-term potentiation (Collingridge and Bliss, 1987), synaptic plasticity (Tsumoto et al., 1987), excitotoxicity through excessive Ca2+ in¯ux (Rothman and Olney, 1987; Meldrum and Garthwaite, 1990), ischaemic brain damage (Albers et al., 1992), and epilepsy (Croucher et al., 1982; Dingledine et al., 1986). These postulated roÃles suggest that the NMDA receptor may be involved in some of the acute and chronic e€ects of ethanol, including cognitive defects, seizures, and neuronal degeneration. 10. Acute e€ects Acute ethanol application in vitro inhibits NMDAstimulated Ca2+ in¯ux and the resultant cyclic GMP accumulation in cultured cells (Ho€man et al., 1989; Wirkner et al., 1999). Ethanol at intoxicating doses (5± 50 mM) inhibits NMDA-induced increases in intracellular Ca2+ in dissociated foetal brain cells (Dildy and Leslie, 1989), the NMDA-receptor-activated ion current in hippocampal neurones (Lovinger et al., 1989), NMDA-receptor-evoked [3H]catecholamine, [3H]acetylcholine and [3H]noradrenaline release in rat striatal and cortical slices, respectively (Gothert and

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Fink, 1989; Gonzales and Woodward, 1990; Woodward and Gonzales, 1990; Brown et al., 1992), and NMDA-induced excitotoxicity in cerebral cortical slices (Lustig et al., 1992) and primary neuronal cultures from rat brain (Chandler et al., 1993b). Ethanol also caused a selective attenuation of K+-evoked glutamate and aspartate release from hippocampal CA1 slices (Martin and Swartzwelder, 1992). Ethanol interferes with the access of MK801 to its intra-channel site by reducing the average probability of channel opening. Although a relatively small e€ect, the resulting reduction in Ca2+ in¯ux and subsequent alteration in the associated intra-neuronal response would be sucient to lead to aberrant neurotransmission (Lima-Landman and Albuquerque, 1989; Spuhler-Phillips et al., 1995). The potency for inhibition of NMDA-activated current by several alcohols linearly correlates with their intoxicating potency (Lovinger et al., 1989). In vivo application of ethanol to the inferior colliculus and hippocampus, but not the lateral septum, potently inhibits NMDA-evoked neuronal activity in a current-dependent manner (Simson et al., 1993). NMDA-evoked neuronal activity in the medial septum (Simson et al., 1991), glutamate-, NMDA-, and quisqualate-induced excitation of rat locus coeruleus neurones (Engberg and HajoÂs, 1992b) and NMDA-induced seizure activity (Kulkarni et al., 1990; Danysz et al., 1992) are inhibited by acute ethanol administration. Ethanol inhibits NMDA-induced increases in cyclic GMP production (Ho€man et al., 1989). Presynaptic inhibition by ethanol has also been demonstrated. The precise site of ethanol's action at the NMDA receptor is not known. Ethanol in vitro has little e€ect …IC50 ˆ 814 mM) on [3H]MK801 binding to wellwashed rat brain membranes (Reynolds and Rush, 1990), which suggests that the inhibition of function is not mediated by direct competition in the channel. Ethanol does not appear to compete at NMDA (Rabe and Tabako€, 1990; Dildy-May®eld and Leslie, 1991), channel (Ho€man et al., 1989), polyamine (Matsumoto et al., 1993a) or Mg2+ sites (Rabe and Tabako€, 1990; Morrisett et al., 1991), but may alter the kinetics of channel opening (Snell et al., 1993; Spuhler-Phillips et al., 1995). The e€ects of ethanol are reversed by glycine in cerebellar granule cells (Ho€man et al., 1989; Rabe and Tabako€, 1990; Iorio et al., 1992) and in cortex and hippocampus (Snell et al., 1993), although an interaction with glycine is not always observed in the latter regions (Gonzales and Woodward, 1990; Weight et al., 1991; Peoples and Weight, 1992). It appears that this interaction does not involve competition (Snell et al., 1993); rather, ethanol and other nalcohols may bind to a hydrophobic pocket (Peoples and Weight, 1995). Using haloperidol-insensitive but MK801-sensitive

binding of [3H]TCP to synaptic membranes, Michaelis et al. (1996) showed ethanol produced a concentrationdependent decrease in the maximal activation of [3H]TCP by glutamate and glycine. 100 mM ethanol completely inhibited the activation of [3H]TCP binding by high concentrations of L-glutamate (200±400 mM) as well as strongly inhibiting the activation of binding by polyamines and glycine. As the synaptic membranes isolated by this group do not have monoclonal nor polyclonal antibody recognition sites against the NR1 protein, this adds to the existing complexity of potential site of action of ethanol. In addition to inhibiting picrotoxin-induced convulsions and reducing the consequent mortality, ethanol also reduces the mortality from NMDA-induced convulsions (Kulkarni et al., 1990). Ethanol at high doses inhibits pentylenetetrazole-induced c-fos expression in rat brain (Le et al., 1990). Acute injection of ethanol blocks the actions of pentylenetetrazole and NMDA without a€ecting the response to kainic acid or caffeine, suggesting that ethanol blockade of c-fos expression is mediated by actions at both the NMDA and GABA receptors (Le et al., 1992). MK801 prevents the increased c-fos mRNA expression which occurs during ethanol withdrawal in rat dentate gyrus and pyriform cortex (Morgan et al., 1992). 11. Recombinant studies Recombinant NMDA receptors expressed in Xenopus ooÈcytes show ethanol sensitivity comparable to that seen in neurones. NR1B homomeric assemblies are more sensitive than homomeric NR1A sets. Heteromeric NR1/NR2A and NR1/NR2B complexes are more sensitive than NR1/NR2C combinations (Koltchine et al., 1993; Kuner et al., 1993; Masood et al., 1994; Mirshahi and Woodward, 1995). This order of sensitivity is not a€ected by modulatory agents such as Mg2+, Zn2+ or glycine antagonists, or by the redox state (Chu et al., 1995). However, at sub-saturating glycine concentrations, NR1/NR2C and NR1/NR2D receptors can be inhibited by ethanol (Buller et al., 1995). This may be an important observation with regard to regional di€erences in ethanol sensitivity. A trimeric assembly which may more closely approximate native receptors was not signi®cantly more sensitive to ethanol inhibition than the dimeric combinations (Mirshahi and Woodward, 1995). The inclusion of an NR2C subunit in a trimeric combination, however, conferred a lower sensitivity to ethanol. The NR1/ NR2D combination was found to be the most insensitive of the four dimeric sets (Chu et al., 1995). Ethanol sensitivity of NR1/2A receptors expressed in ooÈcytes and HEK 293 cells was markedly enhanced under conditions of elevated Ca2+. Enhancement was dependent

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on the presence of the C0 domain (approximately 30 amino acids between the end of transmembrane region IV and the start of C1 cassette) of the NR1 subunit and was also NR2-dependent, which suggests an interaction between the receptor and an intracellular regulatory process (Mirshahi et al., 1998). 12. Chronic e€ects Chronic exposure of the brain to ethanol leads to up-regulation of the NMDA receptor and its responses in vivo in the rat (Chen et al., 1997b), and increases the number of glutamate binding sites in synaptosomal membranes prepared from rat brain (Michaelis et al., 1978). There is a modest (25±50%) increase in the number of MK801 binding sites in the hippocampus (Grant et al., 1990; Sanna et al., 1993; Snell et al., 1993), and variable changes in cortex, striatum, and thalamus (Gulya et al., 1991). Glutamate binding is also increased but CGS-19755 and glycine-site binding is not altered by chronic ethanol treatment (Snell et al., 1993). Expression of the mRNA encoding the NR1 subunit has been reported to be unaltered in rat brain following chronic ethanol administration (Follesa and Ticku, 1995), although NR1 subunit immunoreactivity is increased in the hippocampus (Trevisan et al., 1994), ventral tegmental area (Ortiz et al., 1995) and cerebellum (Snell et al., 1996a). In contrast, NR2A mRNA expression is either unchanged (Snell et al., 1996a) or increased (Follesa and Ticku, 1995), while protein expression (Snell et al., 1996a) is increased, in rat cortex and hippocampus. These con¯icting ®ndings may be explained by translation control of NR2A protein expression (Wood et al., 1996). Expression of the NR2B mRNA is increased in the cortex and hippocampus (Follesa and Ticku, 1995). A recent study con®rmed the increase in NR2B after chronic ethanol and also reported alteration in the balance of the 5' splice variants in favour of the NR2A type although no changes in the 3 ' splice variants were detected (Hardy et al., 1999). Studies in vitro show that chronic ethanol increases the NMDA/glycine-induced Ca2+ in¯ux (Iorio et al., 1992) and sensitizes cultured cerebral granule cells and cortical neurones to the excitotoxic e€ects of NMDA application (Chandler et al., 1993a; Iorio et al., 1993). Increased MK801 binding in chronically ethanolexposed cultured cortical neurones is re¯ected by increased NR1 and NR2B subunit immunoreactivity (Follesa and Ticku, 1996). Chronic ethanol treatment of cultured cortical neurones enhances the NMDAmediated increase in intracellular Ca2+ ion concentration and in parallel increased [3H]MK801 binding (Hu and Ticku, 1995). As the chronic attenuation of glutamate trans-

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mission results in the compensatory up-regulation of NMDA receptors, ethanol withdrawal would be expected to be associated with an increase in excitatory amino acid transmission. Withdrawal from chronic ethanol exposure generates seizures, especially after an audiogenic or handling stimulus. Hippocampal MK801 binding sites are increased at the initiation of ethanol withdrawal, remain elevated during the period of peak withdrawal hyperactivity, and return to control levels 24 h after withdrawal (Grant et al., 1990; Gulya et al., 1991; Snell et al., 1993), although another study showed no change in [3H]MK801 binding to hippocampal membranes from ethanol-dependent rats killed 3 h after the last ethanol exposure (Sanna et al., 1993). Ethanol-dependent rats tested during withdrawal (9±24 h after last ethanol exposure) were more sensitive to seizures induced by either NMDA or kainic acid and the increased activity of NMDA-mediated transmission during withdrawal was paralleled by a signi®cant increase in [3H]MK801 binding in the hippocampus (Sanna et al., 1993). Ethanol withdrawal in the rat also leads to a selective increase in extracellular glutamate release, which acamprosate blocks (Dahchour et al., 1998). Administration of a glutamate antagonist, glutamate diethyl ester, attenuates withdrawal behaviours (Freed and Michaelis, 1978). MK801 suppresses spontaneous seizures and decreases the likelihood of audiogenicallyinduced seizures (Freed and Michaelis, 1978; Morrisett et al., 1990; Grant et al., 1990, 1992) as can antagonists at the polyamine and glycine sites (Kotlinska and Liljequist, 1996). Ethanol withdrawal potentiates NMDA-induced damage to the hippocampus (Davidson et al., 1993, 1995). The increased number of MK801 binding sites in the hippocampus (Gulya et al., 1991) and elevated NR2 subunit mRNA expression (Follesa and Ticku, 1995) return to control with the same time course as ethanol withdrawal seizures. The competitive NMDA receptor antagonist, CGP-39551, is a potent inhibitor of withdrawal seizures and hyperexcitability (Liljequist, 1991; Ripley and Little, 1995). Considerable increases in the severity of the withdrawal hyperexcitability and an increased incidence of seizures is seen if CGP-39551 is given chronically along with ethanol. These results suggest that chronic administration of CGP-39551 increases the adaptive changes that cause or contribute to ethanol-withdrawal hyperactivity (Ripley and Little, 1995). Just as glutamate antagonists reduce the severity of ethanol withdrawal, administration of agonists such as NMDA during the withdrawal period increased the severity of withdrawal (Grant et al., 1990; Davidson et al., 1993). Ethanol withdrawal causes an up-regulation of glutamate transmission in the locus coeruleus (the major noradrenergic nucleus of the brain), increasing the activity of the noradrenergic system (Engberg and HajoÂs, 1992a).

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This may contribute to the autonomic instability, behavioural agitation and psychosis seen during ethanol withdrawal in human cases. The link between NMDA receptors and ethanol withdrawal seizures was further strengthened by the ®nding that MK801 binding sites were at higher density in ethanol-naive withdrawal-seizure-prone mice than in matched withdrawal-seizure-resistant animals (Valverius et al., 1990), although no di€erences in the sensitivity of [3H]MK801 binding to glycine or polyamines were detected. No change in the density of the [3H]MK801 binding site or its anity was detected after 24 h of ethanol vapour inhalation in these animals (Carter et al., 1995). [3H]MK801 binding in membrane preparations from alcohol-non-tolerant and alcohol-tolerant rats showed no signi®cant di€erences (Nakki et al., 1995). These contrasting results suggest that NMDA receptor characteristics may need long periods of intoxication to change (Carter et al., 1995).

13. Adaptive changes in subunit combinations Di€erential NR1 splicing or NR2 subunit expression may confer regional speci®city. Chronic exposure of rats to ethanol results in a dramatic up-regulation of NR1 subunit protein in the hippocampus, but not in any other brain area (Trevisan et al., 1994). There are signi®cant increases in the levels of NR2A and NR2B subunit mRNA in the hippocampus and cerebral cortex (Follesa and Ticku, 1995; Hardy et al., 1999) but NR2C mRNA does not change in the cerebellum (Follesa and Ticku, 1995). Although NR1 subunit mRNA concentration is invariant across brain regions, the balance of the 5 ' splice variants is altered (Hardy et al., 1999). In vivo, Kalluri et al. (1998) showed 135% increases in NR1, NR2A and NR2B expression in both cortex and hippocampus. These returned to control levels by 48 h after the last ethanol dose. Chronic ethanol treatment was associated with a region-speci®c up-regulation of NR1 and NR2A subunit proteins in

Table 1 Changes induced by ethanol in NMDA receptor parameters in animal modelsa Model

Hippocampus mouse in vivo " " rat in vivo " " " " " " Cortex mouse in vivo " " rat in vivo " " " " " mouse in vitro " " rat in vitro " Cerebellum mouse in vivo mouse in vitro rat in vivo a

mRNA/polypeptide expressed NR1

NR2A

0/+

0/+

/+ 0/ /+

+/ /+

0/0

0/+

/0 0/ +/ 0/#

+/

MK801 binding NR2B

NR2C

+ + +/ /+

0/

+ + + 0 0 + 0

+/ +/ +/

0/ 0/+

0/ 0/0

+/ +/+

/0 0/+

/0 0/+

/0 0/+

0/+ 0/ 0/

0/0 0/ 0/

0/

Reference

0/ 0 0 + + 0

0/

0, no change; +, increase;  during withdrawal; #, change in splice variant.

Snell et al., 1996a Gulya et al., 1991 Snell et al., 1993 Trevisan et al., 1994 Follesa and Ticku, 1995 Kalluri et al., 1998 Valverius et al., 1990 Sanna et al., 1993 Carter et al., 1995 Rudolph et al., 1997 Snell et al., 1996a Gulya et al., 1991 Valverius et al., 1990 Trevisan et al., 1994 Follesa and Ticku, 1995 Kalluri et al., 1998 Hardy et al., 1999 Carter et al., 1995 Rudolph et al., 1997 Hu et al., 1996 Follesa and Ticku, 1996 Hu and Ticku, 1995 Chandler et al., 1997 Chandler et al., 1999 Snell et al., 1996a Ho€man et al., 1996 Follesa and Ticku, 1995

P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

mice (Snell et al., 1996a). Detailed analysis of regional changes in subunit expression using in situ hybridization histochemistry and quantitative immunohistochemistry will be needed to reveal regional or subregional di€erences in responses to chronic ethanol treatment in vivo. A summary of the available information is set out in Table 1. Chronic ethanol treatment of primary cultures of cerebral cortical neurones produces a selective up-regulation of NR2B subunit mRNA levels, while NR2A and NR1 mRNA expression levels are not altered (Hu et al., 1996). Treatment of cell cultures with MK801 or AP5 up-regulates NR2B mRNA expression levels (Hu et al., 1996) and NMDA binding sites (Williams et al., 1992); the antagonists reverse the up-regulation produced by chronic ethanol exposure (Hu et al., 1996). Raised NR1 and NR2B polypeptide levels, and increased NR2B mRNA concentration, are found after chronic ethanol treatment in foetal cortical neurones (Follesa and Ticku, 1996). Ethanol stabilizes the NR1 mRNA and enhances the rate of NR2B gene transcription (Kumari and Ticku, 1998). Chronic ethanol treatment of mouse cortical neurones in culture is reportedly accompanied by increased expression of NR1 and NR2B polypeptide subunits (Snell et al., 1996a). Chandler et al. (1997), however, found no changes in NR1, NR2A or NR2B protein levels, or [125I]MK801 binding, in neuronal cultures exposed to chronic ethanol conditions. They did report a potentiation of NMDA-stimulated nitric oxide formation with this treatment (Chandler et al., 1997). 14. The glycine co-agonist site The inhibitory e€ect of ethanol on NMDA receptors in cultured cerebral granule cells is antagonized by high concentrations of glycine, suggesting that ethanol acts close to the glycine binding site (Ho€man et al., 1989). Glycine reverses the ethanol inhibition of NMDA-stimulated increases in intracellular Ca2+ ion concentration (Dildy-May®eld and Leslie, 1991) and reverses the ethanol inhibition of NMDA-induced release of endogenous dopamine from striatal slices (Woodward and Gonzales, 1990). Exogenous glycine reverses the inhibition by ethanol of NMDA-activated Ca2+ ¯uxes in cerebellar granule cells (Rabe and Tabako€, 1990). Ethanol does not inhibit membrane glycine binding, but glycine does reverse the inhibition of [3H]MK801 binding by ethanol under non-equilibrium conditions (Snell et al., 1993). There is a stronger glycine reversal of ethanol inhibition in NR1/ NR2A, NR1/NR2C or NR1/NR2D combinations than in NR1/NR2B complexes (Buller et al., 1995). The reversal is not complete, suggesting a multi-component mechanism of action (Buller et al., 1995). The

521

interaction between ethanol and glycine also seems to depend on brain area, since hippocampal and cortical slices showed no glycine reversal of the ethanolmediated inhibition of neurotransmitter release, whereas glycine reversed the e€ects of ethanol on dopamine release in striatal slices (Gonzales and Brown, 1995). The inhibition of NMDA-activated current by ethanol in rat hippocampal neurones does not involve a competitive interaction with glycine (Peoples and Weight, 1992). Ethanol-mediated inhibition of NMDA-stimulated [3H]noradrenaline release from hippocampal slices is not due to simple competition at the glycine site, and is not blocked by 7-chlorokynurenate (Woodward, 1994a). Glycine does not reverse ethanolmediated inhibition of NMDA responses in cerebrocortical cells (Bhave et al., 1996), nor signi®cantly increase the EC50 for glycine in ooÈcytes expressing recombinant receptors (Mirshahi and Woodward, 1995). Glycine fails to reverse ethanol-mediated inhibition of glutamate-stimulated increases in intracellular Ca2+ ion concentrations in dissociated whole-brain neonatal neurones (Morris and Leslie, 1996). Ethanol's inhibition of NMDA-induced currents in ooÈcytes expressing NR1/NR2A or NR1/NR2C subunits is not altered by glycine concentrations up to 100 mM (Mirshahi and Woodward, 1995). The degree of ethanol inhibition was not a€ected in NR1B/NR2A receptors in the presence of 10 or 100 mM glycine (Chu et al., 1995). In summary, the varied ability of glycine to reverse the ethanol-mediated inhibition of NMDA receptors may re¯ect di€erences in endogenous glycine levels between brain regions or cell culture preparations as well as the nature of subunit expression in native receptors. 15. Other modulatory sites 15.1. Redox Treatment of rat brain slices pre-loaded with [3H]noradrenaline with dithiothreitol greatly potentiates NMDA-stimulated release, but only slightly reduces the inhibition produced by ethanol, whereas 55 '-dithio-bis(2-nitrobenzoic acid) signi®cantly enhances ethanol's potency as an NMDA antagonist (Woodward, 1994b). This suggests that the redox state of the NMDA receptor may be important in determining its sensitivity to ethanol (Woodward, 1994b). 15.2. Mg2+ Mg2+ ions potentiate the inhibition by ethanol of NMDA-mediated depolarizations in hippocampal cells

522

P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

(Martin et al., 1991). The action of ethanol on the NMDA receptor is voltage-independent (Weight et al., 1993) and it does not signi®cantly alter the Mg2+ block of the receptor (Gonzales and Woodward, 1990; Woodward and Gonzales, 1990). Ethanol's inhibitory potency is reduced in ooÈcytes expressing either NR1[N616Q]/NR2A or NR1[N616R]/NR2A mutant receptors, which have a reduced Ca2+ permeability and a reduced sensitivity to Mg2+ block (Mirshahi and Woodward, 1995). Di€erences in ion permeation characteristics may account for the di€erences in sensitivity to ethanol between NR2A- and NR2C-containing receptors. Ethanol sensitivities of NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptor combinations are una€ected by Mg2+ (Chu et al., 1995). Ethanol does not alter the sensitivity of the NMDA response to inhibition by Mg2+ in primary cultures of cerebrocortical cells (Bhave et al., 1996). 15.3. Polyamines Interest has been drawn towards the NR2B mRNA up-regulation after chronic ethanol administration, and the link between ifenprodil-sensitive and ethanolsensitive neurones and the polyamine-sensitive NR2B subunit. Ethanol-mediated inhibition of NMDA receptor function during the development in culture of neocortical neurones from 16±17-day rat embryos decreases in parallel to a decrease in ifenprodil-induced inhibition (Lovinger, 1995). Although ethanol preferentially inhibits the function of ifenprodil-sensitive receptors, it seems unlikely that ethanol and ifenprodil compete for a site on the receptor; rather, the molecular properties of ifenprodil-sensitive NMDA receptors may allow for enhanced ethanol sensitivity (Lovinger, 1995). Neuronal ifenprodil-sensitive receptors contain the NR2B subunit (Williams, 1993; Lovinger, 1995). NMDA-evoked release of neurotransmitters is inhibited in a concentration-dependent manner by ethanol; the potency of inhibition correlates with the inhibitory potency of ifenprodil (Fink and Gothert, 1996). When the activity of ethanol and ifenprodil on responses to NMDA were compared in individual neurones in several brain regions, ethanol inhibited responses in a subgroup of neurones in which ifenprodil inhibited the NMDA-induced increase in ®ring rate (Yang et al., 1996). Although not all ifenprodil-sensitive responses are ethanol-sensitive, any neurone that is insensitive to ifenprodil antagonism has also been found to be nonresponsive to ethanol (Yang et al., 1996). The selective interaction of acamprosate with polyamine sites seems to be an important part of its anti-craving action, and chronic ethanol exposure in rats may alter NMDA receptor expression to modulate acamprosate response (al Qatari et al., 1998; Berton et al., 1998). HEK 293 cells transfected with NR1/NR2A/NR2B

subunits show an enhanced sensitivity to ifenprodil inhibition following a 24 h exposure to ethanol, indicating an increase in the number of NR2B subunits in the mature heteromeric NMDA receptor complex without an alteration in the total pool of NR2B subunits present in the membrane (Blevins et al., 1997). The inhibitory e€ect of ethanol on the NMDA response in cultured cerebellar granule cells involves a receptor population component with apparent potency for ifenprodil in the submicromolar range, with functional and pharmacological properties of the NR2B subtype (Engblom et al., 1997). Eliprodil (a polyamine receptor antagonist) causes a dose-related inhibition of ethanol withdrawal-induced audiogenic seizures, indicating that the NR2B subunit may be particularly important for the modulation of seizure activity in this paradigm (Kotlinska and Liljequist, 1996). Because NMDA receptors sensitive to ifenprodil contain the NR2B subunit, it is plausible that the NMDA isoreceptor sensitive to ethanol antagonism also contains this subunit. A study of chronic ethanol treatment and polyamine homeostasis in the rat revealed that ethanol dependence is associated with increases in the activity of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) and with polyamine levels in several brain regions. The injection of a suicide inhibitor of ornithine decarboxylase was found to block ethanol withdrawal behaviours (Davidson and Wilce, 1998). This study indicated that withdrawal of ethanol exposes cells to increased levels of polyamines, which may act in concert with an up-regulated and polyamine-sensitive NMDA receptor to generate hypersensitivity. Behavioural studies indicate the involvement of polyamines in convulsant activity produced by NMDA receptor agonists (Singh et al., 1990b; Matsumoto et al., 1993a; Davidson et al., 1996), and this argues for a modulatory roÃle for polyamines in their interaction is with the NMDA receptor during withdrawal in rats. 16. Ethanol and NMDA-induced excitotoxicity Glutamate is a toxic agent and its interaction with both acute and chronic ethanol administration has been studied as a model of alcohol-induced brain damage. Excessive stimulation of neurones can trigger a sequence of events that lead to increased intracellular Ca2+ ion concentration by various mechanisms, including in¯ux through voltage-dependent and receptor-gated channels, intracellular release from internal stores, and decreased bu€ering within the cell (Davidson et al., 1990). Glutamate-gated ion channels are candidates for the neuropathological consequences of excessive receptor stimulation. Ethanol, like conventional NMDA receptor antagonists, attenuates excitotoxic neuronal injury in di€erent cell preparations

P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

(Takadera et al., 1990; Lustig et al., 1992; Chandler et al., 1993a). Ethanol added with NMDA to rat cortical cell cultures prevented the cytotoxic e€ects of NMDA caused by receptor-mediated Ca2+ in¯ux (Takadera et al., 1990). Chronic exposure of cerebellar granule and cerebrocortical cells to ethanol results in signi®cantly increased cytotoxic response to glutamate (Chandler et al., 1993b; Iorio et al., 1993). This predisposition or sensitization of neurones to excitotoxicity by chronic ethanol exposure has implications for the pathobiology of ethanol-induced brain damage caused by excessive alcohol consumption over a lifetime. Studies exploring mechanisms for this sensitization have shown that NMDA-receptor-mediated toxicity correlates with intracellular Ca2+ ion concentration (Ahern et al., 1994). Addition of NMDA antagonists prevents both the increase in intracellular Ca2+ ion concentration and the cytotoxic actions of glutamate in cerebellar granule cells (Ho€man et al., 1995). Chronic exposure of hippocampal neurones in culture to ethanol increases cell death mediated by NMDA, but not that mediated by AMPA or KA exposure or altered by the presence of the voltage-sensitive calcium channel antagonist nifedipine (Smothers et al., 1997). In vivo, application of NMDA to the hippocampus after chronic ethanol results in increases in both the severity of the behavioural response and neuronal cell death (Davidson et al., 1993, 1995).

17. Non-NMDA receptors and ethanol The e€ects of ethanol on AMPA/KA receptors are less well characterized than those on NMDA receptors. Chronic ethanol treatment leads to a supersensitivity to kainate-induced seizures (Freed and Michaelis, 1978). Ethanol inhibits AMPA/KA receptors, but this inhibition usually occurs at ethanol concentrations higher than those required to inhibit NMDA receptors (Ho€man et al., 1989; Lovinger et al., 1989; Dildy-May®eld and Harris, 1992b). While non-NMDA receptors are generally less sensitive to ethanol inhibition, some studies have indicated a speci®c e€ect on KA receptors. Ethanol can inhibit at least a sub-population of AMPA and KA receptors expressed in Xenopus ooÈcytes, which develop tolerance to this e€ect upon chronic in vitro ethanol exposure (Dildy-May®eld and Harris, 1992a, 1992b). Ethanol inhibits AMPA and kainate-induced depolarization of hippocampal neurones (Lovinger, 1993a; Martin et al., 1995). Ethanol-withdrawn rats are more sensitive to the convulsant e€ects of kainate injection (Sanna et al., 1993), although ethanol does not protect against kainate-induced seizures (Kulkarni et al., 1990; Le et al., 1992). The expression of the GluR1 subunit is

523

increased in the ventral tegmental area during chronic ethanol treatment (Ortiz et al., 1995). The kainate-induced current in hippocampal neurones is inhibited by only 18% by ethanol (50 mM), whereas the NMDA-induced current is inhibited by 61% (Lovinger et al., 1989). Ethanol inhibits kainateinduced [3H]NA over¯ow in a functional assay with an IC50 of 126 mM (Fink and Gothert, 1990). The e€ect of ethanol on kainate-induced currents is dependent on kainate concentration, in that the inhibition is greater at low concentrations, suggesting a di€erential ethanol sensitivity of KA receptor subunits (DildyMay®eld and Harris, 1992b). Systemic kainate administration causes limbic seizures and widespread irreversible neuronal damage in speci®c brain regions mostly associated with the limbic system (Sperk, 1994). The seizures and neuronal damage are blocked by NMDA receptor antagonists (Berg et al., 1993; Matsumoto et al., 1996), implying that kainate-induced depolarization relieves the Mg2+ blockade of the NMDA receptor (Mayer et al., 1984; Nowak et al., 1984). The damage can be limited to the CA sub®elds of the hippocampus and the entorhinal cortex by reducing the animal's body temperature (Matsumoto et al., 1996). By lesioning limbic areas with kainate, the involvement of NMDA-mediated neurotransmission in certain ethanol withdrawal behaviours could be demonstrated (Matsumoto et al., 1996). Chronic ethanol administration has no signi®cant e€ect on the number of [3H]kainate binding sites in either cortex or hippocampal membrane preparations (Snell et al., 1993). Speci®c antisera to GluR1 and GluR2 revealed no di€erences in subunit expression in speci®c brain areas of rats exposed to chronic ethanol treatment (Trevisan et al., 1994). However, altered di€erential expression of AMPA receptor mRNA transcripts has been observed after chronic, long-term alcohol administration in the rat (Bruckner et al., 1997). Repeated alcohol withdrawal after two day periods of complete intoxication was found to be accompanied by down-regulation of AMPA binding sites in several brain regions, with no or only minor changes in regional NMDA-, KA- or benzodiazepine-binding densities (Ulrichsen et al., 1996). Ethanol acts more potently on recombinant AMPA/KA receptors than on endogenous receptors (Lovinger, 1993a). The sensitivity of various subtypes of the AMPA/KA channels is very similar (Lovinger, 1993a; Dildy-May®eld and Harris, 1995). Both homomeric and heteromeric kainate-sensitive channels are inhibited by ethanol with varying sensitivity depending on subunit components and kainate concentration. The inhibition of kainate responses expressed in ooÈcytes involves two mechanisms, one protein kinase C-independent and one protein kinase C-dependent, under conditions of elevated

524

P.R. Dodd et al. / Neurochemistry International 37 (2000) 509±533

intracellular Ca2+ ion concentration (Dildy-May®eld and Harris, 1995). Although less research has been concentrated on the non-NMDA receptors, a picture of ethanol sensitivity that under the right conditions corresponds to NMDA receptor sensitivity is beginning to emerge.

extent of this involvement is elucidated, new pharmacotherapies to ameliorate these conditions are beginning to be de®ned. It is a challenge for research in this ®eld to continue this process with the range of precise and sensitive techniques now available, so that the new therapies can be soundly based and properly targetted.

18. Human studies

Acknowledgements

In animal model studies, increases in NMDA receptor binding such as those discussed above do not always occur under other chronic ethanol treatment protocols and in di€erent animal strains (Rudolph et al., 1997). Although it is now realised that a wide range of paradigms may be applied to autopsied brain tissue (Dodd et al., 1988), few studies on excitatory amino acid neurotransmission and the pathogenesis of alcohol-related brain damage have been carried out. NMDA receptor antagonists have been reported to have ethanol-like acute subjective e€ects in human subjects (Krystal et al., 1998), and glutamate-mediated transmission in the brain has been strongly argued to play a part in alcoholism (Tsai and Coyle, 1998). Studies of human brain samples obtained at autopsy from chronic alcoholics have shown contrasting results. Dodd et al. (1992) found no di€erence from controls in [3H]MK801 binding to membranes from superior frontal cortex, while Freund and Anderson (1999) found no di€erences in an autoradiographic investigation of several brain regions. Michaelis et al. (1990) reported increased [3H]glutamate binding in the hippocampus of alcoholics, but Cummins et al. (1990) found a 9% decrease in NMDA-speci®c glutamate binding and Crews et al. (1993) showed a decrease in [3H]MK801 binding in this tissue. Michaelis et al. (1993) found an apparent increase in the total number of glutamate binding sites, but a decrease in NMDA receptor density. There is autopsy-based evidence that AMPA/KA receptor subunit expression di€ers in alcoholics and control cases, and that brain regions are selectively a€ected (Breese et al., 1995). It is clear that much more work is needed in this area. Studies of both NMDA and non-NMDA receptors will be markedly advanced by the systematic application of emerging molecular techniques.

We thank the NHMRC and the Australian Associated Brewers for Financial Support. PRD is an NHMRC Principal Research Fellow.

19. Conclusions There is an abundance of evidence to suggest that excitatory amino acid neurotransmission is heavily involved in the adaptive responses that underlie the pathogenesis of alcoholic brain damage and altered states such as alcohol dependency. As the nature and

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