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The Ibogaine Dossier
The Ibogaine Dossier

NYU Conference on Ibogaine Nov 5-6, 1999

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The Ibogaine Dossier

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Review articles describing the NMDA-receptor

1. The psychopharmacology of hallucinogens. Abraham, H.D., Aldridge, A.M. and Gogia, P. Neuropsychopharmacology 14:285-298, 1996.

Abstract: The strychnine-insensitive glycine site on the N-methyl-D- aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2- one), a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T- maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA-966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7-chlorkynurenic acid, did not substitute for (+)- HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did not substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine- like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 17742 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists

2. Ibogaine block of the NMDA receptor - in vitro and in vivo studies. Chen, K., Kokate, T.G., Donevan, S.D., Carroll, F.I. and Rogawski, M.A. Neuropharmacology 35:423-431, 1996.

Abstract: 1. Ibogaine, a proposed anti-addictive agent, has been found to interfere with the acquisition of a weak morphine-induced place preference. The present series of experiments determined if ibogaine would interfere with the expression of a previously established morphine (5 mg/kg) place preference. 2. A single injection of 40 mg/kg of ibogaine 24 h, 12 h or 4 h prior to the preference test (Experiment 1) or 80 mg/kg of ibogaine 24 hr prior to the preference test (Experiment 3) did not interfere with the expression of a morphine conditioned place preference. 3. Furthermore two injections of 40 mg/kg of ibogaine 48 h and 24 h or 24 h and 4 h prior to testing (Experiment 2) did not interfere with the expression of a morphine place preference. 4. Ibogaine appears to be incapable of attenuating the expression of a previously established one-trial morphine place preference. [References: 27]

3. [New therapeutic possibilities with low-affinity NMDA receptor antagonists]. [Review] [German]. Kornhuber, J. and Weller, M. Nervenarzt. 67:77-82, 1996.

4. The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine. Sershen, H., Hashim, A. and Lajtha, A. Brain Res Bull 40:63-67, 1996.

Abstract: The indole alkaloid ibogaine has been suggested to have potential for inhibiting dependency on stimulant drugs. Radioligand binding studies have suggested possible multisite actions of ibogaine: affinity at the kappa-opioid, NMDA, and sigma receptors, with effects on dopamine (DA) release. To further investigate the multiplicity of sites of action of ibogaine and the presynaptic regulation of the DA release, the effect of ibogaine on NMDA- and sigma-receptor-mediated efflux of [H-3]DA was measured in striatal tissue from C57BL/6By mice. Striatal tissue was incubated in vitro with [H-3]DA and the effect on DA release was measured. Both NMDA (25 mu M) and the sigma receptor agonist (+/-)-pentazocine (20 mu M) alone increased the efflux of DA. (+/-)-Pentazocine (100 nM) did not inhibit the NMDA-evoked release. MK-801 (5 mu M) completely inhibited the NMDA-evoked release and inhibited the (+/-)- pentazocine-evoked release by 49%. Ibogaine (10 mu M) itself increased the efflux of DA; at 1 mu M it was without effect. Ibogaine (1 mu M) inhibited the NMDA-evoked release of DA by 31% and inhibited the (+/-)-pentazocine-evoked release by 48%. In addition, the level of basal release of DA obtained after the NMDA- or (+/-)-pentazocine-evoked-release remained higher in the tissue exposed to ibogaine throughout. The results suggest that sigma receptors can regulate the release of DA, along with an action at the NMDA receptor. We previously reported action of ibogaine at the kappa-opioid site. The elevated basal release of DA in the presence of ibogaine after NMDA-or (+/-)-pentazocine- evoked release may reflect the ibogaine-induced removal of the tonically active kappa-opioid system that acts presynaptically to reduce dopamine release. The kappa-opioid system also appears to be inhibitory on both the NMDA and sigma receptors

5. The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine. Sershen, H., Hashim, A. and Lajtha, A. J Neurochem 66:S59, 1996.

6. Antagonists of the NMDA receptor-channel complex and motor coordination. [Review]. Carter, A.J. Life Sci 57:917-929, 1995.

Abstract: Glutamate receptor antagonists with selective action at the N- methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neuropsychiatric disorders. Although NMDA receptor antagonists of the phencyclidine (PCP) type are precluded from clinical use because of their psychotomimetic properties, amantadine and memantine have been administered to human patients with idiopathic Parkinson's disease and spasticity for many years without serious adverse effects. The mechanisms underlying these differences in psychotogenicity of different NMDA receptor antagonist are currently being discussed. Different affinity to the PCP binding site of the NMDA receptor, region-specific pharmacology, as well as different binding profiles to neurotransmitter receptors other than the NMDA type glutamate receptor, most likely play a role in determining whether an NMDA receptor antagonist drug will be tolerated clinically or not. [References: 22]

7. The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. [Review]. Ellison, G. Brain Res Brain Res Rev 20:250-267, 1995.

8. Properties of Ibogaine and Its Principal Metabolite (12 Hydroxyibogamine) at the mK 801 Binding Site of the NMDA Receptor Complex. Mash, D.C., Staley, J.K., Pablo, J.P., Holohean, A.M., Hackman, J.C. and Davidoff, R.A. Neurosci Lett 192:53-56, 1995.

Abstract: The putative anti-addiction alkaloid ibogaine and its principal metabolite 12-hydroxyibogamine appear to act at the (+)-5 methyl- 10,11-dihydro-5H-dibenzo[a,d]cycloheten-5-10 maleate (MK-801) binding site in the N-methyl-D-aspartate (NMDA)- receptor cation channel. This conclusion is based on findings that both compounds competitively displaced specific [H-3]MK-801 binding to membranes from postmortem human caudate and cerebellum and from frog spinal cord. Ibogaine was 4-6-fold more potent than its metabolite and both compounds were less potent (50-1000-fold) than MK-801 binding to the NMDA receptor. In addition, ibogaine (100 mu M) and 12-hydroxyibogamine (1 mM) blocked (85-90% of control) the ability of NMDA (100 mu M, 5 s) to depolarize frog motoneurons in the isolated frog spinal cord. The prevention of NMDA- depolarizations in frog motoneurons showed use-dependency and was very similar to the block produced by MK-801. In view of the abilities of MK-801 to affect the responses to addictive substances in pre-clinical investigations, our results are compatible with the idea that the ability of ibogaine and 12- hydroxyibogamine to interrupt drug-seeking behavior may, in part, result from their actions at the MK-801 binding site

9. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. [Review]. Muller, W.E., Mutschler, E. and Riederer, P. Pharmacopsychiatry 28:113-124, 1995.

Abstract: Our current knowledge of the structure and function of NMDA receptors is expanding at a rapid pace; however, advances regarding regulation of the supply of glutamate and its co- agonist, glycine, have been slower. While the anatomical sources and metabolic compartmentation of glutamate have been studied, limited efforts have been dedicated to defining the dynamics and compartmentation of the co-agonist, glycine. In fact, most investigators have made the assumption that glycine is freely available, via diffusion, for synaptic transmission at NMDA-type synaptic clefts. This assumption ignores the intricate inactivation mechanisms potentially involved in regulating synaptic levels of this amino acid and the recent descriptions of high levels of endogenous D-serine, another potential agonist of the NMDA-associated glycine receptor, in the brain. In this review, the relevance of these data and pharmacological experiments pertinent to the question of whether the NMDA- associated glycine receptor is saturated in vivo or not, is presented. [References: 62]

10. Neuroprotective properties of the uncompetitive NMDA receptor antagonist remacemide hydrochloride. [Review]. Palmer, G.C., Cregan, E.F., Borrelli, A.R. and Willett, F. Ann NY Acad Sci 765:236-247, 1995.

Abstract: There is a growing body of evidence that disturbances of glutamatergic neurotransmission may underlie the pathomechanism and cognitive deficits of Alzheimer's disease. This review describes the potential use of low affinity, noncompetitive NMDA receptor antagonists in the treatment of this disease using memantine as an example. Evidence is presented indicating that this class of compound is neuroprotective in preclinical models of subchronic glutamate toxicity without producing side effects characteristic for other classes of NMDA receptor antagonist. This is attributed to their fast blocking kinetics and strong voltage dependency. Memantine also produces symptomatological improvement of cognition in animal models. The mechanism of action of this effect is still unclear but might be related to an enhancement of AMPA receptor mediated neurotransmission. In patients with dementia syndrome of various aetiologies, memantine produces a rapid onset, clinical improvement in various symptomatological deficits. [References: 90]

11. NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine. Popik, P., Layer, R.T., Fossom, L.H., et al. J Pharmacol Exp Ther 275:753-760, 1995.

Abstract: Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D- aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (K-i, 2.3 mu M at -60 mV). Consistent with this observation, ibogaine competitively inhibits [H-3]1-[1-(2- thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (K-i, 1.5 mu M) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 mu M). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED(50), 64.9 mg/kg) in mice trained to discriminate the prototypic voltage- dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone- precipitated jumping in morphine-dependent mice (ED(50), 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone- precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative ''antiaddictive'' property of this alkaloid, its ability to reduce the expression of morphine dependence

12. Excitotoxicity and the NMDA receptor--still lethal after eight years. [Review]. Rothman, S.M. and Olney, J.W. Trends Neurosci 18:57-58, 1995.

13. NMDA and D1 receptors mediate induction of c-fos and junB genes in striatum following morphine administration: implications for studies of memory. [Review]. Sharp, F.R., Liu, J., Nickolenko, J. and Bontempi, B. Behav Brain Res 66:225-230, 1995.

Abstract: Although it has been known for several decades that the administration of amphetamines to experimental animals produces damage to monoaminergic neurons, the mechanism(s) underlying this neuropathology is unknown. In recent years, it has been demonstrated that various N-methyl-D-aspartate (NMDA) receptor antagonists can prevent the damage produced by the amphetamines. The purpose of this communication is to review the evidence which demonstrates the role of NMDA receptors in the neuropathology of neostriatal dopaminergic neurons produced by the amphetamines and to discuss how the action of the amphetamines may potentially affect NMDA receptor function. [References: 27]

14. The role of N-methyl-D-aspartate receptors in dopaminergic neuropathology produced by the amphetamines. [Review]. Sonsalla, P.K. Drug Alcohol Depend 37:101-105, 1995.

Abstract: Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion- channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez- like circuit. [References: 140]

15. Discriminative Stimulus Effects of R (+) 3 Amino 1 Hydroxypyrrolid 2 One, ((+) Ha 966), a Partial Agonist of the Strychnine Insensitive Modulatory Site of the N Methyl D Aspartate Receptor. Witkin, J.M., Brave, S., French, D. and Geterdouglass, B. J Pharmacol Exp Ther 275:1267-1273, 1995.

Abstract: The strychnine-insensitive glycine site on the N-methyl-D- aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-5-amino-1-hydroxypyrrolid- 2-one], a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T-maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA- 966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7- chlorkynurenic acid, did not substitute for (+)-HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did riot substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine-like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 17742 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists

16. The co-agonist concept: is the NMDA-associated glycine receptor saturated in vivo?. [Review]. Wood, P.L. Life Sci 57:301-310, 1995.

Abstract: Many structurally different, centrally active antagonists of the NMDA receptor-channel complex induce phencyclidine-like side effects in mammals which include head weaving, body rolling, sniffing and disturbances of motor coordination. The ability of these compounds to cause disturbances of motor coordination correlates directly with their ability to antagonize the NMDA receptor-channel complex in vivo. Although noncompetitive antagonists increase motility in rodents, whereas competitive antagonists do not, both classes of compounds appear to induce schizophrenia-like psychosis in human beings, and cause similar changes in a variety of different biogenic amine neurotransmitter systems in the limbic and motoric areas of the brain. The complex spectrum of behavioural effects observed after the administration of antagonists of the NMDA receptor-channel complex probably reflects the intricate nature of the interaction with positive and negative feedback loops of the motor circuit. Recent research indicates that the site of integration of this interaction could be the striatal medium spiny GABAergic neuron. [References: 160]

17. Regulation by neuroprotective factors of NMDA receptor mediated nitric oxide synthesis in the brain and retina. [Review]. Akaike, A., Tamura, Y., Terada, K. and Nakata, N. Prog.Brain Res 103:391-403, 1994.

Abstract: The glutamate transmitter system provides several benevolent/malevolent paradoxes. Glutamate itself serves vitally important functions in the CNS but has enormous neurodestructive potential. NMDA glutamate receptor antagonists protect many neurons against glutamate neurotoxicity, while injuring or destroying certain other neurons and inducing psychotic symptoms and memory impairment. Therefore, the challenge in developing protective therapies against glutamate's neurodestructive potential is to find benevolent agents that are not malevolent as well. There are two possible approaches. One is to develop neuroprotective agents that are free from neuropsychopathological side effects; the other is to use NMDA antagonists even though they have neuropsychopathological side effects, but to use them in combination with other agents that block the side effects without producing side effects of their own. [References: 79]

18. Assessing structural changes in the brain to evaluate neurotoxicological effects of NMDA receptor antagonists. [Review]. Auer, R.N. Psychopharmacol.Bull 30:585-591, 1994.

Abstract: This article serves as an introduction to the following two articles which describe the effects of drugs that interact with N- methyl-D-aspartate (NMDA) receptors on a number of behavioral baselines. The discussion in the subsequent articles focuses on detailed examination of performance on complex learning tasks, although effects of drugs affecting NMDA receptors on simple learned and unlearned behaviors are also mentioned. This article will provide a framework for interpretation of the results reported. To that end, a short primer on the principles of behavior is provided, followed by a description of a number of behavioral tests and discussion of issues important for the interpretation of results from such tests. The behavioral baselines discussed are, for the most part, the specific tasks from which data are presented in the following reports. A few additional descriptions have been included to illustrate specific points regarding data interpretation. The examples discussed are not necessarily representative of behavioral endpoints used routinely in the assessment of the behavioral effects of drugs. A number of reviews are available to the interested reader (Cabe & Eckerman 1982; Heise 1984; Rice 1990; Thompson & Shuster 1968; World Health Organization 1986). [References: 23]

19. [Neuronal protection in neurologic diseases?]. [Review] [German]. Bahr, M., Eschweiler, G.W. and Dichgans, J. Nervenarzt. 65:355-360, 1994.

20. Effects of NMDA receptor antagonists on the developing brain. [Review]. Constantine-Paton, M. Psychopharmacol.Bull 30:561-565, 1994.

Abstract: Electrophysiologic responses to the glutamate agonist analogue N- methyl-D-aspartate (NMDA) are enhanced in the developing nervous system compared to responses in the adult. Neurotoxicity mediated by comparable amounts of NMDA and its endogenous analogue quinolinate is more than 50 times greater in the 7-day-old rat brain than in the adult. NMDA antagonist drugs reduce this neurotoxicity with the same spectrum of activity with which they prevent injury from hypoxic-ischemic damage. The greater vulnerability of the immature brain to NMDA mediated injury is probably related to the enhanced role that NMDA mechanisms play in long-term potentiation and activity-dependent plasticity during development. [References: 54]

21. The impact of NMDA receptor antagonists on learning and memory functions. [Review]. Cory-Slechta, D.A. Psychopharmacol.Bull 30:601-612, 1994.

Abstract: The c-fos and junB immediate early genes (IEGs) were induced in neurons of the medial and ventral striatum following administration of morphine. The striatal induction of c-fos and junB mRNA and Fos protein was blocked by naloxone, the D1 dopamine (DA) receptor antagonists, SCH23390 and SCH39166, and the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, MK801. SCH23390 and MK801 did not block morphine induction of c- fos and junB in septum. Since the pattern of the morphine induction of c-fos and junB in striatum and nucleus accumbens was similar to that observed with cocaine and amphetamine [2,18,45, 51], these data support current concepts that limbic striatum and nucleus accumbens are among the brain regions that mediate drug abuse [9,10,23,27,49]. If it is true that D1 receptors activate the CRE (cyclase response element) and NMDA receptors activate the SRE (serum response element) in the c-fos promoter [1], then this data suggests that serial activation of mu opiate, NMDA and D1 receptors on different neurons is required to induce Fos in striatal neurons with D1 Moreover, concurrent activation of NMDA and D1 receptors is required for Fos induction in striatal neurons. The Fos induced by this simultaneous activation of NMDA and D1 receptors should lead to long-term changes of gene expression that might also be involved in changes of brain circuits that could form the basis for 'memories' relating to prior exposure to addictive drugs. [References: 51]

22. Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology. [Review]. Hargreaves, R.J., Hill, R.G. and Iversen, L.L. Acta Neurochir.Suppl.(Wien). 60:15-19, 1994.

23. [The phencyclidine-N-methyl-D-aspartate theory of schizophrenia: clinical applications]. [Review] [Hebrew]. Heresco-Levy, U., Elman, I. and Javitt, D. Harefuah. 126:598-601, 1994.

Abstract: Several types of lesions of the mature central nervous system (CNS), such as craniocerebral trauma or spinal cord trauma, may initiate secondary cascades, which may cause damage to primarily uninjured neurons. The exact mechanisms which cause neuronal cell death are still unknown. It has been suggested that retrogradely transported target-derived neurotrophic factors which are necessary for neuronal survival might be lacking after certain types of lesions. On the other hand, neurons might be damaged by calcium-overload resulting from excessive release of excitatory amino acids (EAAs) after trauma. The present review summarizes current concepts of post-traumatic neuronal cell damage with a focus on the putative neuroprotective role of calcium channel blockers and their interaction with glutamate mediated cytotoxicity, neurotrophic factors and free radicals. [References: 50]

24. Pharmacological evidence for a role of long-term potentiation in memory. [Review]. Izquierdo, I. FASEB J 8:1139-1145, 1994.

Abstract: The focus of this article will be on toxic symptoms associated with blockade of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. We have been studying two parallel phenomena: NMDA-antagonist neurotoxicity (NAN) in rats and NMDA-antagonist psychotogenicity (NAP) in humans. These phenomena have a common denominator--NMDA receptor hypofunction, which is putatively a mechanism operative in schizophrenia. We have found that the NAN reaction in rats can be prevented by specific drugs that prevent NAP in humans and by certain antipsychotic agents, including clozapine, that ameliorate symptoms in schizophrenia. By studying mechanisms by which clozapine prevents the NAN reaction in rats, we hope to gain insight into mechanisms by which clozapine or other atypical antipsychotics ameliorate symptoms in schizophrenia. [References: 26]

25. Developmental aspects of NMDA receptor agonists and antagonists in the central nervous system. [Review]. Johnston, M.V. Psychopharmacol.Bull 30:567-575, 1994.

Abstract: Like all pharmacologic agents known, N-methyl-D-aspartate (NMDA) antagonist compounds have side effects. It is expected that neuroactive molecules have effects, including side effects, in the central nervous system (CNS). With NMDA antagonists in rodents, these side effects are remarkably focal in the cingulate and retrosplenial cortex. The salient features of NMDA antagonist neurotoxicity which should be underscored are hypermetabolism, lactate accumulation, neuronal vacuolization in aldehyde fixed material, and neuronal death in older rodents. The scope of this phenomenon must urgently be determined in non-rodent species, specifically primates. This is important from both a regulatory and neurotherapeutic point of view, since effective molecules having potential in human disease states may also have NMDA antagonist properties. [References: 27]

26. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. [Review]. Kornhuber, J., Weller, M., Schoppmeyer, K. and Riederer, P. J Neural Transm.Suppl. 43:91-104, 1994.

27. The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. [Review]. Leeson, P.D. and Iversen, L.L. J Med Chem 37:4053-4067, 1994.

Abstract: Age-related changes of N-methyl-D-aspartate (NMDA) receptors have been found in cortical areas and in the hippocampus of many species. On the basis of a variety of experimental observations it has been suggested that the decrease of NMDA receptor density might be one of the causative factors of the cognitive decline with aging. Based on these findings several strategies have been developed to improve cognition by compensating the NMDA receptor deficits in aging. The most promising approaches are the indirect activation of glutamatergic neurotransmission by agonists of the glycine site or the restoration of the age-related deficit of receptor density by several nootropics. [References: 40]

28. Laboratory basis of novel therapeutic strategies to prevent HIV-related neuronal injury. [Review]. Lipton, S.A. Res Publ.Assoc.Res Nerv.Ment.Dis. 72:183-202, 1994.

29. Current concepts of ethanol dependence. [Review]. Littleton, J. and Little, H. Addiction. 89:1397-1412, 1994.

Abstract: NMDA receptor-antagonists were tested in dose ranges that have previously been found to produce anticonvulsant and anticataleptic (antiparkinsonian) effects in rats. Non- competitive NMDA receptor-antagonists had strong psychomotor stimulating effects, the competitive ones were weaker in this respect when given systemically. However, when locally injected into the striatum or into the nucleus accumbens, also the competitive NMDA-antagonists induced psychomotor stimulation. If at all, NMDA receptor-antagonists have rewarding effects, then they seem to be elicited only by the non-competitive NMDA receptor-antagonists. In maze tests, sensitive for hippocampally mediated learning, NMDA receptor-antagonists impaired learning. While non-competitive NMDA-antagonists produced learning deficits over the whole dose range tested, competitive ones were only effective at higher dose levels. [References: 33]

30. Therapeutic potential of NMDA antagonists in neurodegenerative diseases. [Review]. McBurney, R.N. Neurobiol.Aging 15:271-273, 1994.

Abstract: Alcohol dependence is considered to be divisible into two types (although the divisions between these are indistinct). These are psychological dependence, in which the rewarding effects of alcohol play a primary role, and chemical dependence, in which adaptive changes in the brain initiate punishing effects on withdrawal of alcohol, and suppression of these becomes the primary motive for using the drug. The neurochemical basis for the rewarding effects of alcohol may be the potentiation of GABA at GABAA receptors (causing relaxation) and release of dopamine from mesolimbic neurones (causing euphoria). The adaptive changes which cause the alcohol withdrawal syndrome are not known for certain, but alterations in GABAA receptors, NMDA receptors and voltage-operated calcium channels all have a claim. However, it is distinctly doubtful whether these all contribute to the negatively reinforcing effects of alcohol that are important in chemical dependence, although they may be important in other pathological effects of alcohol abuse. Current research badly needs better communication between basic scientists and clinicians to establish research goals and to improve current models. [References: 75]

31. Molecular pharmacology of NMDA receptors: modulatory role of NR2 subunits. [Review]. Molinoff, P.B., Williams, K., Pritchett, D.B. and Zhong, J. Prog.Brain Res 100:39-45, 1994.

Abstract: Memory processes and long-term potentiation (LTP) are blocked at the time of their initiation by antagonists of glutamate NMDA or metabotropic receptors, by drugs that hinder the activity of carbon monoxide or the platelet-activating factor, and by GABA type A receptor agonists. In the next 2 h, memory and LTP are accompanied by an enhancement of the activity of calcium/calmodulin-dependent protein kinase II and of protein kinase C, and are blocked by inhibitors of these enzymes. At the time of expression, memory and LTP are blocked by antagonists of glutamate AMPA receptors. The effects of drugs on memory are seen upon their infusion into areas of the brain known to be responsible for the storage and retrieval of declarative memories (hippocampus, amygdala, medial septum, entorhinal cortex) and are both task- and structure-specific. When put together with other pharmacologic findings, with lesion and recording studies, and with data on transgenic animals showing deficits of both memory and LTP, the data reviewed here lend strong support to the hypothesis that LTP in these brain areas underlies memory processes. [References: 66]

32. Glutamatergic treatment strategies for age-related memory disorders. [Review]. Muller, W.E., Scheuer, K. and Stoll, S. Life Sci 55:2147-2153, 1994.

33. Biochemical analysis of glial fibrillary acidic protein as a quantitative approach to neurotoxicity assessment: advantages, disadvantages and application to the assessment of NMDA receptor antagonist-induced neurotoxicity. [Review]. O'Callaghan, J.P. Psychopharmacol.Bull 30:549-554, 1994.

Abstract: This overview describes two effects of N-methyl-D-aspartate (NMDA) receptor antagonists that are not strictly speaking toxic: There are no signs that cells are dying. Nevertheless, these antagonists, if applied for prolonged periods in young children, could permanently cripple normal brain function. Disturbing the function of the NMDA channel during development can severely disrupt the wiring of defined neural circuits. It also can disrupt the developmental upregulation of the receptor protein itself and possibly many other molecular components of the synapse. [References: 49]

34. Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity. [Review]. Olney, J.W. and Farber, N.B. J Clin.Psychiatry 55 Suppl B:43-46, 1994.

Abstract: It has been reported that several uncompetitive NMDA receptor ion channel blocking agents (phencyclidine, ketamine, dizocilpine, dextrorphan) cause transient reversible vacuolation in neurons in the posterior cingulate cortex of rats. Similar effects have also been observed with competitive glutamate antagonists such as CPP, CGS 19755 and CGP 37849. This transient morphological change has been noted to be coincident anatomically with brain regions showing hypermetabolism after administration of uncompetitive NMDA receptor ion channel blockers and competitive glutamate antagonists. These results therefore indicate that the functional consequences of NMDA receptor blockade with competitive glutamate and uncompetitive channel antagonists are ultimately the same. These changes do not appear to be a prelude to irreversible damage except after relatively high doses of the receptor ion channel antagonists but they have given rise to concern over the safety in use of NMDA antagonists as neuroprotective agents. In contrast, vacuolation has not yet been demonstrated with agents acting at the glycine (L-687,414) or polyamine (eliprodil) modulatory sites of the NMDA receptor complex suggesting that agents acting at these sites may have a greater potential therapeutic window. [References: 20]

35. Neurotoxicity of NMDA receptor antagonists: an overview. [Review]. Olney, J.W. Psychopharmacol.Bull 30:533-540, 1994.

Abstract: Hypertrophy appears to be a universal response of astrocytes, a central nervous system (CNS) cell type, to all forms of brain injury. The hallmark of this response, often termed "reactive gliosis," is the enhanced expression of the major intermediate filament protein of astrocytes, glial fibrillary acidic protein (GFAP). Reactive gliosis traditionally has been examined qualitatively by immunohistochemistry of GFAP. But, the widespread availability of enzyme-linked immunosorbent assays (ELISAs) now makes it possible to quantify damage-induced expression of GFAP as a potential biomarker of diverse neurotoxic insults. To evaluate this possibility, we administered prototype neurotoxicants to experimental animals and then assessed the effects of these agents on the tissue content of GFAP, as determined by a recently developed sandwich ELISA. We found that assays of GFAP reveal dose-, time-, and region-dependent patterns of neural damage, often at toxicant dosages below those that cause light microscopic evidence of cell loss or damage. No false positives have been seen following exposure to a variety of pharmacological agents at therapeutic dosages. With respect to NMDA receptor antagonists, we find that MK-801 causes a large dose-dependent increase in GFAP that, within the cortex, appears to be restricted to the retrosplenial zone. Among the advantages of the CFAP-based approach re its simplicity, objectivity, cost and the fact that the assay can be automated. Among the disadvantages are the need to perform brain dissections and the requirement for a time-course analysis.(ABSTRACT TRUNCATED AT 250 WORDS) [References: 18]

36. The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex. Popik, P., Layer, R.T. and Skolnick, P. Psychopharmacology 114:672-674, 1994.

Abstract: Ibogaine is a putative anti-addictive drug with potential efficacy for the treatment of opiate, stimulant, and alcohol abuse. We now report ibogaine is a competitive inhibitor (Ki, 1.01 +/- 0.1 microM) of [3H]MK-801 binding to N-methyl-D- aspartate (NMDA) receptor coupled cation channels. Since MK-801 can attenuate the development of tolerance to morphine and alcohol as well as sensitization to stimulants in preclinical studies, the reported ability of ibogaine to modify drug-seeking behavior in man may be attributable to a blockade of NMDA receptor coupled cation channels

37. Introduction to principles and procedures in behavioral testing. [Review]. Rice, D.C. Psychopharmacol.Bull 30:593-599, 1994.

38. Behavioural effects of NMDA-receptor antagonists. [Review]. Schmidt, W.J. J Neural Transm.Suppl. 43:63-69, 1994.

Abstract: The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor- dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes. [References: 94]

39. Structural requirements for the development of potent N-methyl-D-aspartic acid (NMDA) receptor antagonists. [Review]. Bigge, C.F. Biochem Pharmacol 45:1547-1561, 1993.

40. Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. [Review]. Gentile, N.T. and McIntosh, T.K. Ann Emerg.Med 22:1028-1034, 1993.

41. Pharmacologic regulation of the NMDA receptor-ionophore complex. [Review]. Johnson, K.M., Snell, L.D., Sacaan, A.I. and Jones, S.M. NIDA Res Monogr 133:13-39, 1993.

Abstract: NMDA and non-NMDA (AMPA/kainate) antagonists have potential in the treatment of a diverse group of neurological disorders associated with excessive activation of excitatory amino acid receptors. Here Michael Rogawski reviews recent progress in the development of therapeutically useful NMDA receptor channel blockers and a new class of selective AMPA/kainate receptor antagonists, the 2,3-benzodiazepines. Research on these novel noncompetitive excitatory amino acid antagonists has opened promising new avenues for the development of drugs to treat epilepsy, ischaemia, neurodegeneration and Parkinson's disease. [References: 60]

42. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. [Review]. Lipton, S.A. Trends Neurosci 16:527-532, 1993.

43. Heterocyclic modulators of the NMDA receptor. [Review]. Pellicciari, R., Natalini, B., Costantino, G., et al. Farmaco. 48:151-157, 1993.

Abstract: Ethanol, acutely, is a potent and selective inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in primary cultures of cerebellar granule cells. The effect of ethanol can be reversed by high concentrations of glycine, and nonequilibrium ligand binding studies in brain membrane preparations suggest that ethanol may act by decreasing the frequency of ion channel opening. After chronic consumption of ethanol by animals, the number of NMDA receptors (measured by ligand binding) is increased in many brain areas. Similarly, NMDA receptor function is increased in cerebellar granule cells exposed chronically to ethanol. In the intact animal, this receptor up-regulation may be associated with ethanol withdrawal seizures, which are attenuated by uncompetitive antagonists at the NMDA receptor. In contrast to ethanol, barbiturates have a greater inhibitory effect at the kainate subtype of glutamate receptor than at the NMDA receptor. After chronic barbiturate ingestion, kainate binding is decreased in certain brain areas, while ligand binding to the NMDA receptor is increased. Overall, the pattern of brain area-specific effects of barbiturates on NMDA and kainate receptor function is quite distinct from that of ethanol. [References: 50]

44. Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. [Review]. Rogawski, M.A. Trends Pharmacol Sci 14:325-331, 1993.

Abstract: Several acute and chronic neurological diseases might be mediated, at least in part, via stimulation of excitatory amino acid receptors, such as the N-methyl-D-aspartate (NMDA) receptor. Antagonists of excitatory amino acid receptors ameliorate neurotoxic damage in several animal models of these disorders. This review focuses on the potential for clinically tolerated NMDA receptor antagonists, with emphasis on agents that have been in clinical use for other conditions and that recently have been shown to inhibit NMDA receptor activity by a mechanism of open- channel block or redox modification. [References: 69]

45. Subtypes of NMDA receptors. [Review]. Stone, T.W. Gen.Pharmacol 24:825-832, 1993.

Abstract: Trauma to the central nervous system can lead to primary injuries occurring at the time of impact as well as secondary or delayed injury processes that can result from cellular hypoxia, oligemia/ischemia, edema and swelling, and intracranial hypertension that are manifested over a period of hours to weeks after the initial event. Although the mechanisms underlying delayed tissue injury are poorly understood, they appear to be associated with endogenous neurochemical changes resulting from traumatic nervous system injury. These neurochemical changes may include excessive neurotransmitter release, deregulation of ion homeostasis, and the synthesis, release, or activation of various "autodestructive" neurochemical factors. Experimental studies over the past decade indicate that these alterations mediate important components of the neurochemical cascade leading to central nervous system injury. Furthermore, pharmacologic manipulations of these neurochemical changes have been reported to attenuate secondary central nervous system damage, ameliorate neuronal death, and promote functional recovery after central nervous system injury. This article focuses on the role of excitatory amino acid neurotransmitters, endogenous opioid peptides, and magnesium in the pathophysiology of central nervous system injury and on the therapeutic manipulation of these systems to improve functional outcome after central nervous system injury. [References: 85]

46. Ethanol, sedative hypnotics, and glutamate receptor function in brain and cultured cells. [Review]. Tabakoff, B. and Hoffman, P.L. Behav Genet. 23:231-236, 1993.

47. [NMDA agonists and antagonists]. [Review] [Japanese]. Toki, S. Tanpakushitsu.Kakusan.Koso. 38:1863-1872, 1993.

Abstract: 1. Beginning with electrophysiological evidence for two populations of receptors for N-methyl-D-aspartate (NMDA) which did or did not respond to the agonist quinolinic acid, evidence has grown for such subdivision. 2. Data from binding studies is consistent with differences between three NMDA receptors in the striatum, thalamus and cerebellum with respect to their preferences for agonist or antagonist binding and the modulation of binding by dizocilpine, cations and polyamines. 3. The recent isolation and sequencing of several different molecular species of NMDA receptor supports the view that at least two pharmacologically distinct sites exist, with the cerebellar receptor being unique in the brain. [References: 62]

48. Prevention of post-traumatic excitotoxic brain damage with NMDA antagonist drugs: a new strategy for the nineties. [Review]. Bullock, R., Kuroda, Y., Teasdale, G.M. and McCulloch, J. Acta Neurochir.Suppl.(Wien). 55:49-55, 1992.

Abstract: The design of new heterocyclic derivatives as modulatory agents at EAA receptors is described. In particular, the potent and selective activity at the NMDA receptor of trans-4- hydroxypipecolic acid-4-sulfate, as well as the neuroprotective properties of substituted thiokynurenates, a new class of competitive antagonists at the glycine site of the NMDA receptor complex, are reported. [References: 20]

49. Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design. [Review]. Krogsgaard-Larsen, P. and Hansen, J.J. Toxicol Lett 64-65 Spec No:409-416, 1992.

Abstract: The triad of rigidity, fever, and elevation of serum creatine phosphokinase (CPK) levels, labeled 'neuroleptic malignant syndrome' (NMS), is a dangerous complication of neuroleptic drug treatment. Amantadine was introduced for the pharmacological management of NMS because of its beneficial effects in Parkinson's disease which were attributed to direct or indirect dopaminomimetic properties of amantadine. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of glutamate receptor. Two lines of evidence suggest that amantadine or other NMDA receptor antagonists could be effective drugs for the reversal of NMS symptoms. First, glutamate antagonists restore the balance between glutamatergic and dopaminergic systems when dopaminergic transmission has been antagonized by neuroleptic drugs. Second, by virtue of their effects against rigor and spasticity, NMDA antagonists may reduce increased muscle tone and prevent rhabdomyolysis. In conclusion, NMS may be considered an iatrogenic excitatory aminoacid syndrome which is amenable to NMDA receptor antagonist therapy. [References: 53]

50. Does modulation of glutamatergic function represent a viable therapeutic strategy in Alzheimer's disease?. [Review]. Lawlor, B.A. and Davis, K.L. Biol Psychiatry 31:337-350, 1992.

Abstract: Excitotoxic mechanisms due to overactivity of the amino acid neurotransmitters glutamate and aspartate maybe responsible for brain damage after injury. In this review we examine ischaemia and shear injury, which are relevant to human head injury. The opportunities for treatment using glutamate antagonist drugs are discussed. [References: 36]

51. A rationale for NMDA receptor antagonist therapy of the neuroleptic malignant syndrome. [Review]. Weller, M. and Kornhuber, J. Med Hypotheses. 38:329-333, 1992.

Abstract: Although glutamate dysfunction has been implicated in the pathogenesis of Alzheimer's disease (AD), it is unclear which direction a glutamatergic strategy should take in this illness. Increasing glutamate function may enhance excitotoxicity and neuronal death, whereas decreasing activity in this excitatory amino acid pathway may impair memory processes. Pharmacological modulation of the different NMDA and nonNMDA receptor sites, together with the concept of an agonist versus antagonist approach, are discussed in this review. It would appear that a glutamatergic approach may represent a new and exciting option to pursue in the experimental pharmacotherapeutics of AD. [References: 75]

52. Excitatory amino acids in epilepsy and novel anti-epileptic drugs. [Review]. Chapman, A. and Meldrum, B. Epilepsy Res Suppl. 3:39-48, 1991.

53. NMDA receptor agonists: relationships between structure and biological activity. [Review]. Ebert, B., Madsen, U., Johansen, T.N. and Krogsgaard-Larsen, P. Adv Exp Med Biol 287:483-487, 1991.

Abstract: Recent data on the aptitude of adamantamines to inhibit or to stimulate glutamatergic (NMDA) neuromediation, to display anti- GABAergic and antiglycinergic components (by blocking the Cl- channel), on the one hand, and on the opposition of the central glutamatergic and dopaminergic systems, on the other, could suggest that the glutamatergic (NMDA) or the anti-NMDA activity, exhibited by some adamantamines, could play an important role in the expression of their pharmacological profile. Anti-NMDA properties, for the adamantamines which exhibited them, could be, by themselves or by developing their anti-GABAergic or antiglycinergic components, the first cause of the hypermotility and dopaminomimetic activity induced by these molecules. Glutamatergic (NMDA) component, which could be displayed by some lipophilic or important steric obstruction on azote exhibiting adamantamines, could amplifie the excitating effects of their anti-GABAergic and antiglycinergic components on the limbic system's brain structures (hippocampus, amygdala) and could contribute to the exhibition of hypomotility, fright, agressivity and convulsions. According to these data, which must be amplier confirmed and deeped, it would be possible to envisage the improvement of adamantamines against the Parkinson's disease (when they exhibit anti-NMDA activity) or their use against the Alzheimer's disease and the late stages of the Parkinson's disease (when they exhibit NMDA activity). [References: 75]

54. N-methyl-D-aspartate antagonists in the treatment of Parkinson's disease [see comments]. [Review]. Greenamyre, J.T. and O'Brien, C.F. Arch.Neurol. 48:977-981, 1991.

55. Competitive antagonism of glycine at the N-methyl-D-aspartate (NMDA) receptor. [Review]. Huettner, J.E. Biochem Pharmacol 41:9-16, 1991.

56. Autoradiographic assessment of the effects of N-methyl-D-aspartate (NMDA) receptor antagonists in vivo. [Review]. McCulloch, J. and Iversen, L.L. Neurochem Res 16:951-963, 1991.

57. Phencyclidine, NMDA receptor and schizophrenia. [Review]. Nishikawa, T., Tanii, Y., Umino, A., et al. Yakubutsu.Seishin.Kodo. 11:65-69, 1991.

Abstract: Current long-term treatment of Parkinson's disease is inadequate, and improved symptomatic and neuroprotective therapies are needed. Recent interest has focused on the use of antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in Parkinson's disease. Abnormally increased activity of the subthalamic nucleus is postulated to play a central pathophysiological role in the signs of Parkinson's disease, and NMDA antagonists may provide a means of decreasing this activity selectively. Like dopaminergic agonists, NMDA antagonists can reverse the akinesia and rigidity associated with monoamine depletion or neuroleptic-induced catalepsy. Very low doses of NMDA antagonists markedly potentiate the therapeutic effects of dopaminergic agonists. There is evidence that the beneficial effects of anticholinergic drugs and amantadine may be mediated, in part, by NMDA receptor blockade. Moreover, NMDA antagonists provide profound protection of dopaminergic neurons of the substantia nigra in the MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) and methamphetamine models of Parkinson's disease. The clinical use of NMDA antagonists may prove useful in Parkinson's disease to treat symptoms and retard disease progression. [References: 72]

58. Effects of quinolinic and kynurenic acids on central neurons. [Review]. Stone, T.W. and Connick, J.H. Adv Exp Med Biol 294:329-336, 1991.

59. [Action mechanism of adamantamines: do their activity on glutamatergic receptors intervene in the expression of their pharmacological profile?]. [Review] [French]. Vamvakides, A. Ann Pharm.Fr. 49:249-257, 1991.

60. Sites for antagonism on the N-methyl-D-aspartate receptor channel complex. [Review]. Wong, E.H. and Kemp, J.A. Annu.Rev Pharmacol Toxicol 31:401-425, 1991.

61. Measuring and controlling the extracellular glycine concentration at the NMDA receptor level. [Review]. Ascher, P. Adv Exp Med Biol 268:13-16, 1990.

62. Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted?. [Review]. Buchan, A.M. Cerebrovasc.Brain Metab.Rev 2:1-26, 1990.

Abstract: There is considerable interest in the development of NMDA antagonists as potential therapeutic agents in the treatment of convulsant, neurodegenerative and anxiety disorders. Because the clinical use of phencyclidine (PCP) has been precluded by its psychotomimetic effects and abuse potential, there has been concern that other NMDA antagonists including those acting competitively might produce similar untoward effects. However, the studies in animals, reviewed here by Joyce Willetts, Robert Balster and David Leander, suggest that while there are certain similarities in the behavioral effects of PCP-like and competitive antagonists, there are also differences. These differences have implications for the development of NMDA antagonists with less likelihood for producing PCP-like side- effects. [References: 42]

63. Quinoxalinediones as excitatory amino acid antagonists in the vertebrate central nervous system. [Review]. Davies, S.N. and Collingridge, G.L. Int.Rev Neurobiol. 32:281-303, 1990.

64. CGP 37849 and CGP 39551: novel competitive N-methyl-D-aspartate receptor antagonists with potent oral anticonvulsant activity. [Review]. Fagg, G.E., Olpe, H.R., Schmutz, M., et al. Prog.Clin.Biol Res 361:421-427, 1990.

Abstract: Perinatal cerebral asphyxia, which results in significant neurologic and cognitive disabilities in infants and children, remains a major health problem. Potential neurologic sequelae include cerebral palsy, mental retardation, and epilepsy. Over the next few years, neuroprotective agents that prevent asphyxial neuronal injury and death are likely to be developed. These agents may also be effective in prophylaxis and treatment of chronic neurologic disorders, including epilepsy and neurodegenerative disorders, such as Huntington disease. [References: 50]

65. Results of N-methyl-D-aspartate antagonists in perinatal cerebral asphyxia therapy. [Review]. Ford, L.M. Pediatr.Neurol. 6:363-366, 1990.

66. Therapeutic potential of NMDA receptor antagonists as neuroprotective agents. [Review]. Foster, A.C., Gill, R., Iversen, L.L., Kemp, J.A., Wong, E.H. and Woodruff, G.N. Prog.Clin.Biol Res 361:301-329, 1990.

67. The behavioral pharmacology of NMDA receptor antagonists [see comments]. [Review]. Willetts, J., Balster, R.L. and Leander, J.D. Trends Pharmacol Sci 11:423-428, 1990.


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