TY - JOUR AU - Abraham,H.D. AU - Aldridge,A.M. AU - Gogia,P. TI - The psychopharmacology of hallucinogens KW - ibogaine KW - drug receptor binding KW - discriminative stimulus KW - animal behavior KW - psychopharmacology KW - instrumental conditioning KW - drug selectivity KW - drug effect KW - binding affinity KW - dose response KW - sedation KW - ataxia KW - nonhuman KW - Male KW - MOUSE KW - animal experiment KW - controlled study KW - intraperitoneal drug administration KW - priority journal KW - article KW - n methyl dextro aspartic acid receptor KW - glutamate receptor agonist KW - Analysis KW - Comparative Study KW - drug dose KW - pd [pharmacology] KW - 3 amino 1 hydroxy 2 pyrrolidinone KW - 1 aminocyclopropanecarboxylic acid KW - cycloserine KW - n methyl dextro aspartic acid receptor blocking agent KW - pd KW - [pharmacology] KW - dizocilpine KW - ifenprodil KW - 2 amino 4,5 (1,2 cyclohexyl) 7 phosphonoheptanoic acid KW - Strychnine KW - Glycine KW - SITES KW - RECEPTORS KW - RECEPTOR COMPLEX KW - COMPLEX KW - Agonists KW - Mice KW - BEHAVIOR KW - Food KW - D-CYCLOSERINE KW - ANTAGONIST KW - HA-966 KW - NMDA Receptor KW - Ion Channels KW - Phencyclidine KW - Hallucinogens JO - Neuropsychopharmacology PY - 1996 AB - 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 RP - NOT IN FILE SP - 285 EP - 298 VL - 14 ER - TY - JOUR AU - Chen,K. AU - Kokate,T.G. AU - Donevan,S.D. AU - Carroll,F.I. AU - Rogawski,M.A. TI - Ibogaine block of the NMDA receptor - in vitro and in vivo studies KW - ibogaine KW - Addiction KW - conditioning KW - craving KW - learning KW - Morphine KW - place preference KW - Reinforcement KW - Reward KW - nmda receptor antagonist.impairs acquisition.rats.mk-801. KW - MEMORY KW - PREFERENCE KW - NMDA Receptor KW - RECEPTORS KW - In Vitro JO - Neuropharmacology PY - 1996 AB - 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] RP - NOT IN FILE SP - 423 EP - 431 VL - 35 ER - TY - JOUR AU - Kornhuber,J. AU - Weller,M. TI - [New therapeutic possibilities with low-affinity NMDA receptor antagonists]. [Review] [German] KW - NMDA Receptor KW - review KW - RECEPTORS JO - Nervenarzt. PY - 1996 RP - NOT IN FILE SP - 77 EP - 82 VL - 67 ER - TY - JOUR AU - Sershen,H. AU - Hashim,A. AU - Lajtha,A. TI - The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine KW - ibogaine KW - NMDA Receptor KW - Sigma Receptor KW - Pentazocine KW - MK-801 KW - Dopamine Release KW - Striatum (Mouse) KW - INDUCED LOCOMOTOR STIMULATION KW - Dopamine KW - Neurons KW - Cocaine KW - Brain KW - Mice KW - Rats KW - Indoles KW - alkaloid KW - In Vitro KW - Agonists KW - RECEPTORS KW - RELEASE KW - indole alkaloid KW - DRUGS KW - Radioligand Binding KW - Kappa-Opioid KW - Sigma Receptors KW - SITES KW - RECEPTOR AGONIST KW - SYSTEM JO - Brain Res Bull PY - 1996 AB - 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 RP - NOT IN FILE SP - 63 EP - 67 VL - 40 ER - TY - JOUR AU - Sershen,H. AU - Hashim,A. AU - Lajtha,A. TI - The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine KW - ibogaine KW - Sigma Receptor KW - RECEPTORS KW - NMDA Receptor KW - Dopamine KW - RELEASE JO - J Neurochem PY - 1996 RP - NOT IN FILE SP - S59 EP - S59 VL - 66 ER - TY - JOUR AU - Carter,A.J. TI - Antagonists of the NMDA receptor-channel complex and motor coordination. [Review] KW - NMDA Receptor KW - review KW - aged KW - alzheimer's disease KW - Drug Therapy KW - Physiopathology KW - amantadine KW - Adverse Effects KW - Therapeutic Use KW - Antiparkinson Agents KW - English Abstract KW - excitatory amino acid antagonists KW - glutamine KW - Physiology KW - Human KW - memantine KW - n-methylaspartate KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - receptors,phencyclidine KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - Phencyclidine KW - MECHANISMS KW - Binding Sites KW - SITES KW - Pharmacology KW - Neurotransmitter Receptors KW - DRUGS KW - COMPLEX JO - Life Sci PY - 1995 AB - 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] RP - NOT IN FILE SP - 917 EP - 929 VL - 57 ER - TY - JOUR AU - Ellison,G. TI - The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. [Review] KW - NMDA Receptor KW - review KW - Animal KW - excitatory amino acid antagonists KW - Toxicity KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - drug effect KW - ANTAGONIST KW - Phencyclidine KW - dizocilpine JO - Brain Res Brain Res Rev PY - 1995 RP - NOT IN FILE SP - 250 EP - 267 VL - 20 ER - TY - JOUR AU - Mash,D.C. AU - Staley,J.K. AU - Pablo,J.P. AU - Holohean,A.M. AU - Hackman,J.C. AU - Davidoff,R.A. TI - Properties of Ibogaine and Its Principal Metabolite (12 Hydroxyibogamine) at the mK 801 Binding Site of the NMDA Receptor Complex KW - ibogaine KW - Hydroxyibogamine KW - MK-801 KW - N-Methyl-D-Aspartate Receptors KW - Spinal Cord KW - Caudate KW - Cerebellum KW - Drug Abuse KW - TOLERANCE KW - BLOCKADE KW - Cocaine KW - Rats KW - ANTAGONIST KW - ETHANOL KW - alkaloid KW - Binding Sites KW - RECEPTORS KW - Human KW - POTENT KW - NMDA Receptor KW - BEHAVIOR KW - RECEPTOR COMPLEX KW - COMPLEX KW - METABOLITES KW - 12-Hydroxyibogamine KW - SITES JO - Neurosci Lett PY - 1995 AB - 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 RP - NOT IN FILE SP - 53 EP - 56 VL - 192 ER - TY - JOUR AU - Muller,W.E. AU - Mutschler,E. AU - Riederer,P. TI - Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Cerebellum KW - Metabolism KW - Glycine KW - Pharmacology KW - Hippocampus KW - Human KW - receptors,glycine KW - Agonists KW - Receptors,N-Methyl-D-Aspartate KW - serine KW - RECEPTORS KW - MECHANISMS KW - Amino Acids KW - D-SERINE KW - GLYCINE RECEPTOR KW - Brain KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - Kinetics JO - Pharmacopsychiatry PY - 1995 AB - 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] RP - NOT IN FILE SP - 113 EP - 124 VL - 28 ER - TY - JOUR AU - Palmer,G.C. AU - Cregan,E.F. AU - Borrelli,A.R. AU - Willett,F. TI - Neuroprotective properties of the uncompetitive NMDA receptor antagonist remacemide hydrochloride. [Review] KW - NMDA Receptor KW - review KW - alzheimer's disease KW - Drug Therapy KW - Physiopathology KW - electrophysiology KW - glutamic acid KW - Physiology KW - Human KW - Ion Channels KW - drug effect KW - neuroprotective agents KW - Therapeutic Use KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - memantine KW - Toxicity KW - Kinetics KW - Animal KW - MECHANISMS JO - Ann NY Acad Sci PY - 1995 AB - 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] RP - NOT IN FILE SP - 236 EP - 247 VL - 765 ER - TY - JOUR AU - Popik,P. AU - Layer,R.T. AU - Fossom,L.H. AU - Benveniste,M. AU - Geterdouglass,B. AU - Witkin,J.M. AU - Skolnick,P. TI - NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine KW - ibogaine KW - INDUCED LOCOMOTOR STIMULATION KW - MORPHINE-TOLERANCE KW - RECEPTOR COMPLEX KW - BEHAVIORAL SENSITIZATION KW - PARASAGITTAL ZONES KW - RAPID TOLERANCE KW - Binding Sites KW - D-SERINE KW - MK-801 KW - Mice KW - HUMANS KW - Addiction KW - Nicotine KW - ANTAGONIST KW - RECEPTORS KW - RAT KW - Naloxone KW - Glycine KW - alkaloid KW - Morphine KW - Morphine Dependence KW - DRUGS KW - NMDA Receptor KW - Cell Death KW - BEHAVIOR KW - discriminative stimulus KW - dizocilpine KW - PRETREATMENT JO - J Pharmacol Exp Ther PY - 1995 AB - 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 RP - NOT IN FILE SP - 753 EP - 760 VL - 275 ER - TY - JOUR AU - Rothman,S.M. AU - Olney,J.W. TI - Excitotoxicity and the NMDA receptor--still lethal after eight years. [Review] KW - NMDA Receptor KW - review KW - acetamides KW - Pharmacology KW - Animal KW - anticonvulsants KW - Brain KW - drug effect KW - Pathology KW - Physiopathology KW - Calcium-Binding Protein,Vitamin D-Dependent KW - Cats KW - cell survival KW - cerebral anoxia KW - Prevention & Control KW - cerebral ischemia,transient KW - cerebrovascular disorders KW - Drug Therapy KW - Disease Models,Animal KW - Human KW - Mice KW - Neurons KW - Cytology KW - Physiology KW - neuroprotective agents KW - parkinson disease KW - Rats KW - Rats,Inbred Strains KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - subarachnoid hemorrhage KW - Excitotoxicity JO - Trends Neurosci PY - 1995 RP - NOT IN FILE SP - 57 EP - 58 VL - 18 ER - TY - JOUR AU - Sharp,F.R. AU - Liu,J. AU - Nickolenko,J. AU - Bontempi,B. TI - NMDA and D1 receptors mediate induction of c-fos and junB genes in striatum following morphine administration: implications for studies of memory. [Review] KW - NMDA Receptor KW - review KW - Amphetamine KW - Toxicity KW - Animal KW - Corpus Striatum KW - drug effect KW - Pathology KW - Dopamine KW - Physiology KW - Dose-Response Relationship,Drug KW - Male KW - methamphetamine KW - Mice KW - Neurons KW - Receptors,N-Methyl-D-Aspartate KW - substantia nigra KW - synaptic transmission KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - Striatum KW - Morphine KW - MEMORY JO - Behav Brain Res PY - 1995 AB - 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] RP - NOT IN FILE SP - 225 EP - 230 VL - 66 ER - TY - JOUR AU - Sonsalla,P.K. TI - The role of N-methyl-D-aspartate receptors in dopaminergic neuropathology produced by the amphetamines. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Behavior,Animal KW - drug effect KW - dementia KW - Chemically Induced KW - Pathology KW - Psychology KW - Disease Models,Animal KW - Dizocilpine Maleate KW - Toxicity KW - Human KW - ketamine KW - Phencyclidine KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - DRUGS KW - MEMORY KW - dizocilpine KW - MK-801 KW - Ion Channels KW - Neurons KW - CORTEX KW - Brain KW - Rats KW - Hippocampus KW - Metabolism KW - ANTAGONIST KW - MECHANISMS KW - Neurotoxicity KW - N-Methyl-D-Aspartate Receptors KW - RECEPTORS KW - Amphetamine KW - alzheimer's disease JO - Drug Alcohol Depend PY - 1995 AB - 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] RP - NOT IN FILE SP - 101 EP - 105 VL - 37 ER - TY - JOUR AU - Witkin,J.M. AU - Brave,S. AU - French,D. AU - Geterdouglass,B. TI - 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 KW - ibogaine KW - NMDA Receptor KW - D-CYCLOSERINE KW - GLYCINE RECEPTOR KW - CHLOROKYNURENIC ACID KW - EXHIBIT ANTIDEPRESSANT KW - XENOPUS OOCYTES KW - ANTAGONIST KW - Convulsions KW - COMPLEX KW - HA-966 KW - Glycine KW - RECEPTORS KW - Agonists KW - Male KW - Mice KW - Food KW - Ion Channels KW - Strychnine KW - discriminative stimulus KW - SITES KW - RECEPTOR COMPLEX KW - BEHAVIOR KW - dizocilpine KW - ifenprodil JO - J Pharmacol Exp Ther PY - 1995 AB - 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 RP - NOT IN FILE SP - 1267 EP - 1273 VL - 275 ER - TY - JOUR AU - Wood,P.L. TI - The co-agonist concept: is the NMDA-associated glycine receptor saturated in vivo?. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Biogenic Amines KW - me [metabolism] KW - Brain KW - excitatory amino acid antagonists KW - pd [pharmacology] KW - gaba KW - Human KW - Motor Activity KW - drug effect KW - Neurons KW - psychomotor performance KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - ANTAGONIST KW - COMPLEX KW - Biogenic Amine KW - SYSTEM KW - SITES KW - Glycine KW - GLYCINE RECEPTOR KW - RECEPTORS KW - Gamma amino butyric acid JO - Life Sci PY - 1995 AB - 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] RP - NOT IN FILE SP - 301 EP - 310 VL - 57 ER - TY - JOUR AU - Akaike,A. AU - Tamura,Y. AU - Terada,K. AU - Nakata,N. TI - Regulation by neuroprotective factors of NMDA receptor mediated nitric oxide synthesis in the brain and retina. [Review] KW - NMDA Receptor KW - review KW - Animal KW - excitatory amino acid antagonists KW - to [toxicity] KW - Human KW - Nerve Degeneration KW - drug effect KW - nervous system diseases KW - Chemically Induced KW - pp [physiopathology] KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - SYSTEM KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - Neurons KW - Neurotoxicity KW - MEMORY KW - neuroprotective agents KW - Brain JO - Prog.Brain Res PY - 1994 AB - 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] RP - NOT IN FILE SP - 391 EP - 403 VL - 103 ER - TY - JOUR AU - Auer,R.N. TI - Assessing structural changes in the brain to evaluate neurotoxicological effects of NMDA receptor antagonists. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Behavior,Animal KW - drug effect KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - article KW - DRUGS KW - RECEPTORS KW - COMPLEX KW - learning KW - BEHAVIOR KW - Brain KW - RECEPTOR ANTAGONIST KW - ANTAGONIST JO - Psychopharmacol.Bull PY - 1994 AB - 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] RP - NOT IN FILE SP - 585 EP - 591 VL - 30 ER - TY - JOUR AU - Bahr,M. AU - Eschweiler,G.W. AU - Dichgans,J. TI - [Neuronal protection in neurologic diseases?]. [Review] [German] KW - NMDA Receptor KW - review KW - Animal KW - Human KW - n-methylaspartate KW - genetics KW - ph [physiology] KW - Receptors,N-Methyl-D-Aspartate KW - Biosynthesis KW - Chemistry KW - drug effect KW - Support,U.S.Gov't,P.H.S. JO - Nervenarzt. PY - 1994 RP - NOT IN FILE SP - 355 EP - 360 VL - 65 ER - TY - JOUR AU - Constantine-Paton,M. TI - Effects of NMDA receptor antagonists on the developing brain. [Review] KW - NMDA Receptor KW - review KW - aging KW - Physiology KW - Animal KW - central nervous system KW - drug effect KW - growth & development KW - Female KW - PREGNANCY KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - Agonists KW - Antagonists & Inhibitors KW - NERVOUS-SYSTEM KW - SYSTEM KW - Adult KW - Neurotoxicity KW - RAT KW - RAT-BRAIN KW - Brain KW - ANTAGONIST KW - DRUGS KW - MECHANISMS KW - RECEPTORS KW - RECEPTOR ANTAGONIST JO - Psychopharmacol.Bull PY - 1994 AB - 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] RP - NOT IN FILE SP - 561 EP - 565 VL - 30 ER - TY - JOUR AU - Cory-Slechta,D.A. TI - The impact of NMDA receptor antagonists on learning and memory functions. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Corpus Striatum KW - drug effect KW - gene expression KW - MEMORY KW - Morphine KW - Pharmacology KW - Morphine Dependence KW - genetics KW - nerve net KW - Neurons KW - proto-oncogene proteins c-fos KW - proto-oncogene proteins c-jun KW - Rats KW - recall KW - Receptors,Dopamine KW - Receptors,N-Methyl-D-Aspartate KW - Receptors,Opioid KW - synaptic transmission KW - Striatum KW - Naloxone KW - Dopamine KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - Nucleus Accumbens KW - Cocaine KW - Amphetamine KW - Brain KW - DRUGS KW - learning JO - Psychopharmacol.Bull PY - 1994 AB - 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] RP - NOT IN FILE SP - 601 EP - 612 VL - 30 ER - TY - JOUR AU - Hargreaves,R.J. AU - Hill,R.G. AU - Iversen,L.L. TI - Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology. [Review] KW - NMDA Receptor KW - review KW - Animal KW - anti-anxiety agents KW - pd [pharmacology] KW - Antipsychotic Agents KW - Binding Sites KW - cognition KW - drug effect KW - Glycine KW - Antagonists & Inhibitors KW - me [metabolism] KW - Human KW - kynurenic acid KW - neuroprotective agents KW - pyrrolidinones KW - Receptors,N-Methyl-D-Aspartate KW - ph [physiology] KW - Structure-Activity Relationship KW - ANTAGONIST KW - Adverse Effects JO - Acta Neurochir.Suppl.(Wien). PY - 1994 RP - NOT IN FILE SP - 15 EP - 19 VL - 60 ER - TY - JOUR AU - Heresco-Levy,U. AU - Elman,I. AU - Javitt,D. TI - [The phencyclidine-N-methyl-D-aspartate theory of schizophrenia: clinical applications]. [Review] [Hebrew] KW - NMDA Receptor KW - review KW - Amino Acids KW - ph [physiology] KW - Animal KW - brain injuries KW - Drug Therapy KW - pp [physiopathology] KW - Calcium Channel Blockers KW - tu [therapeutic use] KW - calcium channels KW - drug effect KW - cell survival KW - English Abstract KW - Human KW - membrane potentials KW - Nerve Degeneration KW - nerve growth factors KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - spinal cord injuries KW - LESIONS KW - central nervous system KW - NERVOUS-SYSTEM KW - SYSTEM KW - Neurons KW - MECHANISMS KW - RELEASE KW - Calcium KW - schizophrenia JO - Harefuah. PY - 1994 AB - 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] RP - NOT IN FILE SP - 598 EP - 601 VL - 126 ER - TY - JOUR AU - Izquierdo,I. TI - Pharmacological evidence for a role of long-term potentiation in memory. [Review] KW - NMDA Receptor KW - review KW - adolescence KW - Adult KW - Animal KW - clozapine KW - pd [pharmacology] KW - excitatory amino acid agonists KW - to [toxicity] KW - Human KW - psychoses,substance-induced KW - Etiology KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - schizophrenia KW - pp [physiopathology] KW - Support,U.S.Gov't,P.H.S. KW - article KW - BLOCKADE KW - RECEPTORS KW - Neurotoxicity KW - HUMANS KW - MECHANISMS KW - DRUGS KW - MEMORY JO - FASEB J PY - 1994 AB - 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] RP - NOT IN FILE SP - 1139 EP - 1145 VL - 8 ER - TY - JOUR AU - Johnston,M.V. TI - Developmental aspects of NMDA receptor agonists and antagonists in the central nervous system. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Brain KW - Pathology KW - brain disease KW - Chemically Induced KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - ANTAGONIST KW - NERVOUS-SYSTEM KW - SYSTEM KW - CORTEX KW - Neurotoxicity KW - Human KW - RECEPTORS KW - RECEPTOR AGONIST KW - Agonists JO - Psychopharmacol.Bull PY - 1994 AB - 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] RP - NOT IN FILE SP - 567 EP - 575 VL - 30 ER - TY - JOUR AU - Kornhuber,J. AU - Weller,M. AU - Schoppmeyer,K. AU - Riederer,P. TI - Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Brain KW - drug effect KW - me [metabolism] KW - Calcium KW - cells,cultured KW - Cholecystokinin KW - pd [pharmacology] KW - tu [therapeutic use] KW - Dopamine KW - eye proteins KW - Mice KW - models,neurological KW - n-methylaspartate KW - Antagonists & Inhibitors KW - nerve tissue proteins KW - Neurotoxins KW - to [toxicity] KW - nitric oxide KW - Biosynthesis KW - oxidation-reduction KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - retina KW - Support,Non-U.S.Gov't KW - amantadine KW - memantine KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST JO - J Neural Transm.Suppl. PY - 1994 RP - NOT IN FILE SP - 91 EP - 104 VL - 43 ER - TY - JOUR AU - Leeson,P.D. AU - Iversen,L.L. TI - The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. [Review] KW - NMDA Receptor KW - review KW - acetamides KW - pd [pharmacology] KW - aging KW - ph [physiology] KW - Animal KW - cognition KW - drug effect KW - cycloserine KW - glutamic acid KW - Human KW - memory disorders KW - Drug Therapy KW - Etiology KW - me [metabolism] KW - px [psychology] KW - n-methylaspartate KW - nootropic agents KW - Receptors,N-Methyl-D-Aspartate KW - RECEPTORS KW - Hippocampus KW - Agonists KW - Glycine KW - SITES KW - Structure-Activity Relationship JO - J Med Chem PY - 1994 AB - 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] RP - NOT IN FILE SP - 4053 EP - 4067 VL - 37 ER - TY - JOUR AU - Lipton,S.A. TI - Laboratory basis of novel therapeutic strategies to prevent HIV- related neuronal injury. [Review] KW - NMDA Receptor KW - review KW - Human KW - n-methylaspartate KW - me [metabolism] KW - Phencyclidine KW - pd [pharmacology] KW - Receptors,N-Methyl-D-Aspartate KW - drug effect KW - schizophrenia KW - Drug Therapy KW - Etiology JO - Res Publ.Assoc.Res Nerv.Ment.Dis. PY - 1994 RP - NOT IN FILE SP - 183 EP - 202 VL - 72 ER - TY - JOUR AU - Littleton,J. AU - Little,H. TI - Current concepts of ethanol dependence. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Behavior,Animal KW - drug effect KW - maze learning KW - Motor Activity KW - Rats KW - reaction time KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Support,Non-U.S.Gov't KW - RECEPTOR ANTAGONIST KW - anticonvulsants KW - Striatum KW - Nucleus Accumbens KW - learning KW - ETHANOL JO - Addiction. PY - 1994 AB - 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] RP - NOT IN FILE SP - 1397 EP - 1412 VL - 89 ER - TY - JOUR AU - McBurney,R.N. TI - Therapeutic potential of NMDA antagonists in neurodegenerative diseases. [Review] KW - NMDA Receptor KW - review KW - Alcohol Drinking KW - pp [physiopathology] KW - px [psychology] KW - Alcoholism KW - Animal KW - Arousal KW - drug effect KW - ph [physiology] KW - Brain KW - gaba KW - Human KW - motivation KW - Receptors,GABA-A KW - Receptors,N-Methyl-D-Aspartate KW - Withdrawal KW - DRUGS KW - RECEPTORS KW - RELEASE KW - Dopamine KW - Calcium KW - ANTAGONIST JO - Neurobiol.Aging PY - 1994 AB - 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] RP - NOT IN FILE SP - 271 EP - 273 VL - 15 ER - TY - JOUR AU - Molinoff,P.B. AU - Williams,K. AU - Pritchett,D.B. AU - Zhong,J. TI - Molecular pharmacology of NMDA receptors: modulatory role of NR2 subunits. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Brain KW - ph [physiology] KW - gaba antagonists KW - pd [pharmacology] KW - long-term potentiation KW - drug effect KW - MEMORY KW - protein kinase c KW - me [metabolism] KW - receptors,metabotropic glutamate KW - Antagonists & Inhibitors KW - Receptors,N-Methyl-D-Aspartate KW - ANTAGONIST KW - RECEPTORS KW - DRUGS KW - PLATELET-ACTIVATING-FACTOR KW - gaba KW - RECEPTOR AGONIST KW - Agonists KW - Hippocampus KW - CORTEX KW - LESIONS KW - Pharmacology JO - Prog.Brain Res PY - 1994 AB - 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] RP - NOT IN FILE SP - 39 EP - 45 VL - 100 ER - TY - JOUR AU - Muller,W.E. AU - Scheuer,K. AU - Stoll,S. TI - Glutamatergic treatment strategies for age-related memory disorders. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Human KW - Nerve Degeneration KW - drug effect KW - ph [physiology] KW - nervous system diseases KW - Drug Therapy KW - pa [pathology] KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - MEMORY JO - Life Sci PY - 1994 RP - NOT IN FILE SP - 2147 EP - 2153 VL - 55 ER - TY - JOUR AU - O'Callaghan,J.P. TI - 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] KW - NMDA Receptor KW - review KW - Animal KW - Brain KW - drug effect KW - growth & development KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - Analysis KW - Neurotoxicity JO - Psychopharmacol.Bull PY - 1994 AB - 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] RP - NOT IN FILE SP - 549 EP - 554 VL - 30 ER - TY - JOUR AU - Olney,J.W. AU - Farber,N.B. TI - Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity. [Review] KW - NMDA Receptor KW - review KW - Animal KW - cell survival KW - drug effect KW - Cerebral Cortex KW - Cytology KW - dextrorphan KW - to [toxicity] KW - Dizocilpine Maleate KW - Dose-Response Relationship,Drug KW - energy metabolism KW - excitatory amino acid antagonists KW - Glycine KW - Antagonists & Inhibitors KW - gyrus cinguli KW - ketamine KW - n-methylaspartate KW - Neurons KW - Phencyclidine KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - vacuoles KW - RECEPTORS KW - Ion Channels KW - dizocilpine KW - CORTEX KW - ANTAGONIST KW - Brain KW - BLOCKADE KW - neuroprotective agents KW - SITES KW - RECEPTOR COMPLEX KW - COMPLEX KW - Neurotoxicity JO - J Clin.Psychiatry PY - 1994 AB - 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] RP - NOT IN FILE SP - 43 EP - 46 VL - 55 Suppl B ER - TY - JOUR AU - Olney,J.W. TI - Neurotoxicity of NMDA receptor antagonists: an overview. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Glial Fibrillary Acidic Protein KW - Analysis KW - me [metabolism] KW - gliosis KW - Drug Therapy KW - Human KW - nervous system diseases KW - Chemically Induced KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Astrocytes KW - central nervous system KW - NERVOUS-SYSTEM KW - SYSTEM KW - Brain KW - Immunohistochemistry KW - Light KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - MK-801 KW - CORTEX KW - Neurotoxicity JO - Psychopharmacol.Bull PY - 1994 AB - 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] RP - NOT IN FILE SP - 533 EP - 540 VL - 30 ER - TY - JOUR AU - Popik,P. AU - Layer,R.T. AU - Skolnick,P. TI - The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex KW - ibogaine KW - Animal KW - Binding,Competitive KW - drug effect KW - Dizocilpine Maleate KW - Antagonists & Inhibitors KW - Pharmacokinetics KW - Pharmacology KW - In Vitro KW - Ion Channels KW - Metabolism KW - Ligands KW - Phencyclidine KW - Analogs & Derivatives KW - Rats KW - Receptors,Glutamate KW - Receptors,N-Methyl-D-Aspartate KW - Morphine KW - DRUGS KW - RECEPTORS KW - MK-801 KW - SENSITIZATION KW - NMDA Receptor KW - RECEPTOR COMPLEX KW - COMPLEX KW - TOLERANCE KW - BEHAVIOR KW - BLOCKADE JO - Psychopharmacology PY - 1994 AB - 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 RP - NOT IN FILE SP - 672 EP - 674 VL - 114 ER - TY - JOUR AU - Rice,D.C. TI - Introduction to principles and procedures in behavioral testing. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Human KW - learning KW - drug effect KW - MEMORY KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors JO - Psychopharmacol.Bull PY - 1994 RP - NOT IN FILE SP - 593 EP - 599 VL - 30 ER - TY - JOUR AU - Schmidt,W.J. TI - Behavioural effects of NMDA-receptor antagonists. [Review] KW - NMDA Receptor KW - review KW - adamantane KW - Analogs & Derivatives KW - pd [pharmacology] KW - po [poisoning] KW - amantadine KW - Animal KW - Behavior,Animal KW - drug effect KW - Dopamine KW - ph [physiology] KW - electrophysiology KW - Hallucinogens KW - Human KW - memantine KW - neuroprotective agents KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Substance Abuse KW - INHIBITION KW - Amino Acids KW - alzheimer's disease KW - ANTAGONIST KW - RECEPTORS KW - Phencyclidine KW - MK-801 KW - DRUGS KW - In Vitro KW - POTENT KW - CONGENERS JO - J Neural Transm.Suppl. PY - 1994 AB - 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] RP - NOT IN FILE SP - 63 EP - 69 VL - 43 ER - TY - JOUR AU - Bigge,C.F. TI - Structural requirements for the development of potent N-methyl-D- aspartic acid (NMDA) receptor antagonists. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Binding Sites KW - biogenic polyamines KW - ph [physiology] KW - Glycine KW - pd [pharmacology] KW - Human KW - Ion Channels KW - drug effect KW - ionophores KW - me [metabolism] KW - n-methylaspartate KW - Phencyclidine KW - receptors,glycine KW - Receptors,N-Methyl-D-Aspartate KW - Support,U.S.Gov't,P.H.S. KW - POTENT KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST JO - Biochem Pharmacol PY - 1993 RP - NOT IN FILE SP - 1547 EP - 1561 VL - 45 ER - TY - JOUR AU - Gentile,N.T. AU - McIntosh,T.K. TI - Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. [Review] KW - NMDA Receptor KW - review KW - Animal KW - bicyclo compounds KW - pd [pharmacology] KW - Binding Sites KW - Binding,Competitive KW - Brain Chemistry KW - Comparative Study KW - drug design KW - glutamates KW - Antagonists & Inhibitors KW - Glycine KW - Ion Channels KW - drug effect KW - models,molecular KW - pyrrolidinones KW - Receptors,N-Methyl-D-Aspartate KW - Chemistry KW - Structure-Activity Relationship KW - ANTAGONIST KW - Amino Acids KW - NERVOUS-SYSTEM KW - SYSTEM JO - Ann Emerg.Med PY - 1993 RP - NOT IN FILE SP - 1028 EP - 1034 VL - 22 ER - TY - JOUR AU - Johnson,K.M. AU - Snell,L.D. AU - Sacaan,A.I. AU - Jones,S.M. TI - Pharmacologic regulation of the NMDA receptor-ionophore complex. [Review] KW - NMDA Receptor KW - review KW - alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid KW - Antagonists & Inhibitors KW - [antagonists & inhibitors] KW - Animal KW - anticonvulsants KW - tu [therapeutic use] KW - benzodiazepines KW - pd [pharmacology] KW - central nervous system diseases KW - Drug Therapy KW - Human KW - Ion Channels KW - receptors,kainic acid KW - Receptors,N-Methyl-D-Aspartate KW - ANTAGONIST KW - Amino Acids KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - DRUGS KW - COMPLEX JO - NIDA Res Monogr PY - 1993 AB - 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] RP - NOT IN FILE SP - 13 EP - 39 VL - 133 ER - TY - JOUR AU - Lipton,S.A. TI - Prospects for clinically tolerated NMDA antagonists: open- channel blockers and alternative redox states of nitric oxide. [Review] KW - NMDA Receptor KW - review KW - Adult KW - Animal KW - aids dementia complex KW - Drug Therapy KW - pa [pathology] KW - Brain KW - drug effect KW - Calcium Channel Blockers KW - Adverse Effects KW - tu [therapeutic use] KW - calcium channels KW - ph [physiology] KW - cell survival KW - child KW - Human KW - hiv-1 KW - py [pathogenicity] KW - Neuroglia KW - Neurons KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Support,Non-U.S.Gov't KW - Support,U.S.Gov't,P.H.S. KW - ANTAGONIST JO - Trends Neurosci PY - 1993 RP - NOT IN FILE SP - 527 EP - 532 VL - 16 ER - TY - JOUR AU - Pellicciari,R. AU - Natalini,B. AU - Costantino,G. AU - Garzon,A. AU - Luneia,R. AU - Mahmoud,M.R. AU - Marinozzi,M. AU - Roberti,M. AU - Rosato,G.C. AU - Shiba,S.A. TI - Heterocyclic modulators of the NMDA receptor. [Review] KW - NMDA Receptor KW - review KW - Alcoholism KW - pp [physiopathology] KW - Animal KW - Brain KW - drug effect KW - cells,cultured KW - Cerebellum KW - ph [physiology] KW - Hypnotics and Sedatives KW - pd [pharmacology] KW - Mice KW - Neurons KW - Receptors,GABA-A KW - Receptors,N-Methyl-D-Aspartate KW - ETHANOL KW - POTENT KW - glutamates KW - RECEPTORS KW - Glycine KW - Ligands KW - Ion Channels KW - Withdrawal KW - ANTAGONIST JO - Farmaco. PY - 1993 AB - 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] RP - NOT IN FILE SP - 151 EP - 157 VL - 48 ER - TY - JOUR AU - Rogawski,M.A. TI - Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Human KW - Ion Channels KW - drug effect KW - nervous system diseases KW - Drug Therapy KW - nitric oxide KW - me [metabolism] KW - oxidation-reduction KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Support,Non-U.S.Gov't KW - Support,U.S.Gov't,P.H.S. KW - Amino Acids KW - RECEPTORS KW - ANTAGONIST KW - RECEPTOR ANTAGONIST KW - MECHANISMS JO - Trends Pharmacol Sci PY - 1993 AB - 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] RP - NOT IN FILE SP - 325 EP - 331 VL - 14 ER - TY - JOUR AU - Stone,T.W. TI - Subtypes of NMDA receptors. [Review] KW - NMDA Receptor KW - review KW - Amino Acids KW - Antagonists & Inhibitors KW - Animal KW - brain injuries KW - Drug Therapy KW - endorphins KW - Human KW - neurotransmitters KW - Receptors,N-Methyl-D-Aspartate KW - spinal cord injuries KW - Support,Non-U.S.Gov't KW - support,u.s.gov't,non-p.h.s. KW - Support,U.S.Gov't,P.H.S. KW - central nervous system KW - NERVOUS-SYSTEM KW - SYSTEM KW - MECHANISMS KW - RELEASE KW - Recovery KW - article KW - RECEPTORS JO - Gen.Pharmacol PY - 1993 AB - 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] RP - NOT IN FILE SP - 825 EP - 832 VL - 24 ER - TY - JOUR AU - Tabakoff,B. AU - Hoffman,P.L. TI - Ethanol, sedative hypnotics, and glutamate receptor function in brain and cultured cells. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Binding Sites KW - Calcium KW - me [metabolism] KW - Cell Death KW - drug effect KW - cells,cultured KW - hyphomycetes KW - Neurons KW - pyrans KW - Chemistry KW - ip [isolation & purification] KW - pd [pharmacology] KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Structure-Activity Relationship KW - ETHANOL KW - glutamates KW - RECEPTORS KW - Brain JO - Behav Genet. PY - 1993 RP - NOT IN FILE SP - 231 EP - 236 VL - 23 ER - TY - JOUR AU - Toki,S. TI - [NMDA agonists and antagonists]. [Review] [Japanese] KW - NMDA Receptor KW - review KW - Animal KW - Brain Chemistry KW - ph [physiology] KW - electrophysiology KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Analysis KW - drug effect KW - RECEPTORS KW - Agonists KW - Striatum KW - Cerebellum KW - PREFERENCE KW - ANTAGONIST KW - dizocilpine KW - SITES KW - Brain JO - Tanpakushitsu.Kakusan.Koso. PY - 1993 AB - 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] RP - NOT IN FILE SP - 1863 EP - 1872 VL - 38 ER - TY - JOUR AU - Bullock,R. AU - Kuroda,Y. AU - Teasdale,G.M. AU - McCulloch,J. TI - Prevention of post-traumatic excitotoxic brain damage with NMDA antagonist drugs: a new strategy for the nineties. [Review] KW - NMDA Receptor KW - review KW - Animal KW - heterocyclic compounds KW - chemical synthesis KW - pd [pharmacology] KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - drug effect KW - RECEPTORS KW - POTENT KW - ANTAGONIST KW - Glycine KW - SITES KW - RECEPTOR COMPLEX KW - COMPLEX KW - Brain KW - DRUGS JO - Acta Neurochir.Suppl.(Wien). PY - 1992 AB - 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] RP - NOT IN FILE SP - 49 EP - 55 VL - 55 ER - TY - JOUR AU - Krogsgaard-Larsen,P. AU - Hansen,J.J. TI - Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design. [Review] KW - NMDA Receptor KW - review KW - amantadine KW - tu [therapeutic use] KW - Human KW - models,biological KW - muscle spasticity KW - Drug Therapy KW - neuroleptic malignant syndrome KW - pp [physiopathology] KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - synaptic transmission KW - drug effect KW - DRUGS KW - ANTAGONIST KW - glutamates KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - SYSTEM KW - Amino Acids KW - Neurotoxins KW - drug design JO - Toxicol Lett PY - 1992 AB - 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] RP - NOT IN FILE SP - 409 EP - 416 VL - 64-65 Spec No ER - TY - JOUR AU - Lawlor,B.A. AU - Davis,K.L. TI - Does modulation of glutamatergic function represent a viable therapeutic strategy in Alzheimer's disease?. [Review] KW - NMDA Receptor KW - review KW - Animal KW - brain damage,chronic KW - pc [prevention & control] KW - pp [physiopathology] KW - brain injuries KW - complications KW - central nervous system agents KW - tu [therapeutic use] KW - cerebral ischemia KW - Dizocilpine Maleate KW - drug screening KW - glutamates KW - Antagonists & Inhibitors KW - ph [physiology] KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - retrograde degeneration KW - drug effect KW - MECHANISMS KW - Amino Acids KW - neurotransmitters KW - Brain KW - ANTAGONIST KW - DRUGS KW - alzheimer's disease JO - Biol Psychiatry PY - 1992 AB - 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] RP - NOT IN FILE SP - 337 EP - 350 VL - 31 ER - TY - JOUR AU - Weller,M. AU - Kornhuber,J. TI - A rationale for NMDA receptor antagonist therapy of the neuroleptic malignant syndrome. [Review] KW - NMDA Receptor KW - review KW - aged KW - alzheimer's disease KW - Drug Therapy KW - pp [physiopathology] KW - px [psychology] KW - Brain KW - drug effect KW - glutamates KW - ph [physiology] KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - receptors,neurotransmitter KW - Support,Non-U.S.Gov't KW - Support,U.S.Gov't,P.H.S. KW - Excitotoxicity KW - Amino Acids KW - MEMORY KW - RECEPTORS KW - SITES KW - Agonists KW - ANTAGONIST KW - RECEPTOR ANTAGONIST JO - Med Hypotheses. PY - 1992 AB - 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] RP - NOT IN FILE SP - 329 EP - 333 VL - 38 ER - TY - JOUR AU - Chapman,A. AU - Meldrum,B. TI - Excitatory amino acids in epilepsy and novel anti-epileptic drugs. [Review] KW - NMDA Receptor KW - review KW - Animal KW - autoradiography KW - cerebral ischemia KW - me [metabolism] KW - deoxyglucose KW - glutamates KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Amino Acids KW - DRUGS JO - Epilepsy Res Suppl. PY - 1991 RP - NOT IN FILE SP - 39 EP - 48 VL - 3 ER - TY - JOUR AU - Ebert,B. AU - Madsen,U. AU - Johansen,T.N. AU - Krogsgaard-Larsen,P. TI - NMDA receptor agonists: relationships between structure and biological activity. [Review] KW - NMDA Receptor KW - review KW - amantadine KW - Chemistry KW - pd [pharmacology] KW - antibodies KW - im [immunology] KW - Antiparkinson Agents KW - English Abstract KW - Glycine KW - gaba KW - n-methylaspartate KW - Receptors,N-Methyl-D-Aspartate KW - drug effect KW - SYSTEM KW - Brain KW - Hippocampus KW - Convulsions KW - alzheimer's disease KW - RECEPTORS KW - RECEPTOR AGONIST KW - Agonists JO - Adv Exp Med Biol PY - 1991 AB - 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] RP - NOT IN FILE SP - 483 EP - 487 VL - 287 ER - TY - JOUR AU - Greenamyre,J.T. AU - O'Brien,C.F. TI - N-methyl-D-aspartate antagonists in the treatment of Parkinson's disease [see comments]. [Review] KW - NMDA Receptor KW - review KW - Amino Acids KW - ph [physiology] KW - Animal KW - brain diseases KW - pp [physiopathology] KW - carboxylic acids KW - pd [pharmacology] KW - Human KW - ibotenic acid KW - Analogs & Derivatives KW - piperidines KW - Receptors,N-Methyl-D-Aspartate KW - drug effect KW - Structure-Activity Relationship KW - Support,Non-U.S.Gov't KW - ANTAGONIST JO - Arch.Neurol. PY - 1991 RP - NOT IN FILE SP - 977 EP - 981 VL - 48 ER - TY - JOUR AU - Huettner,J.E. TI - Competitive antagonism of glycine at the N-methyl-D-aspartate (NMDA) receptor. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Glycine KW - RECEPTORS JO - Biochem Pharmacol PY - 1991 RP - NOT IN FILE SP - 9 EP - 16 VL - 41 ER - TY - JOUR AU - McCulloch,J. AU - Iversen,L.L. TI - Autoradiographic assessment of the effects of N-methyl-D- aspartate (NMDA) receptor antagonists in vivo. [Review] KW - NMDA Receptor KW - review KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST JO - Neurochem Res PY - 1991 RP - NOT IN FILE SP - 951 EP - 963 VL - 16 ER - TY - JOUR AU - Nishikawa,T. AU - Tanii,Y. AU - Umino,A. AU - Hashimoto,A. AU - Hata,N. AU - Takashima,M. AU - Shirayama,Y. AU - Takahashi,K. TI - Phencyclidine, NMDA receptor and schizophrenia. [Review] KW - NMDA Receptor KW - review KW - Dopamine KW - me [metabolism] KW - globus pallidus KW - gaba KW - Human KW - n-methylaspartate KW - Antagonists & Inhibitors KW - nerve tissue proteins KW - neural pathways KW - parkinson disease KW - Drug Therapy KW - pp [physiopathology] KW - Receptors,N-Methyl-D-Aspartate KW - substantia nigra KW - Support,Non-U.S.Gov't KW - Support,U.S.Gov't,P.H.S. KW - trihexyphenidyl KW - tu [therapeutic use] KW - ANTAGONIST KW - glutamates KW - RECEPTORS KW - Agonists KW - DEPLETION KW - DRUGS KW - amantadine KW - BLOCKADE KW - Neurons KW - methamphetamine KW - Phencyclidine KW - schizophrenia JO - Yakubutsu.Seishin.Kodo. PY - 1991 AB - 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] RP - NOT IN FILE SP - 65 EP - 69 VL - 11 ER - TY - JOUR AU - Stone,T.W. AU - Connick,J.H. TI - Effects of quinolinic and kynurenic acids on central neurons. [Review] KW - NMDA Receptor KW - review KW - Animal KW - anticonvulsants KW - tu [therapeutic use] KW - aspartic acid KW - ph [physiology] KW - epilepsy KW - Drug Therapy KW - pp [physiopathology] KW - glutamates KW - Human KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Support,Non-U.S.Gov't KW - synaptic transmission KW - drug effect KW - kynurenic acid KW - Neurons JO - Adv Exp Med Biol PY - 1991 RP - NOT IN FILE SP - 329 EP - 336 VL - 294 ER - TY - JOUR AU - Vamvakides,A. TI - [Action mechanism of adamantamines: do their activity on glutamatergic receptors intervene in the expression of their pharmacological profile?]. [Review] [French] KW - NMDA Receptor KW - review KW - action potentials KW - drug effect KW - Animal KW - Brain KW - convulsants KW - pd [pharmacology] KW - Glycine KW - gaba KW - kynurenic acid KW - models,neurological KW - n-methylaspartate KW - Neurons KW - quinolinic acids KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - ph [physiology] KW - Spinal Cord KW - Support,Non-U.S.Gov't KW - synaptic transmission KW - MECHANISMS KW - RECEPTORS JO - Ann Pharm.Fr. PY - 1991 RP - NOT IN FILE SP - 249 EP - 257 VL - 49 ER - TY - JOUR AU - Wong,E.H. AU - Kemp,J.A. TI - Sites for antagonism on the N-methyl-D-aspartate receptor channel complex. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Binding Sites KW - drug effect KW - Phencyclidine KW - pd [pharmacology] KW - Rats KW - Receptors,Dopamine KW - Receptors,N-Methyl-D-Aspartate KW - schizophrenia KW - Chemically Induced KW - Support,Non-U.S.Gov't KW - SITES KW - N-Methyl-D-Aspartate Receptors KW - RECEPTORS KW - COMPLEX JO - Annu.Rev Pharmacol Toxicol PY - 1991 RP - NOT IN FILE SP - 401 EP - 425 VL - 31 ER - TY - JOUR AU - Ascher,P. TI - Measuring and controlling the extracellular glycine concentration at the NMDA receptor level. [Review] KW - NMDA Receptor KW - review KW - Administration,Oral KW - Animal KW - anticonvulsants KW - Administration & Dosage KW - pd [pharmacology] KW - Binding,Competitive KW - Kinetics KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - me [metabolism] KW - 2-amino-5-phosphonovalerate KW - Analogs & Derivatives KW - Glycine KW - RECEPTORS JO - Adv Exp Med Biol PY - 1990 RP - NOT IN FILE SP - 13 EP - 16 VL - 268 ER - TY - JOUR AU - Buchan,A.M. TI - Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted?. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Behavior,Animal KW - drug effect KW - Phencyclidine KW - pd [pharmacology] KW - Receptors,N-Methyl-D-Aspartate KW - Support,Non-U.S.Gov't KW - Support,U.S.Gov't,P.H.S. KW - ANTAGONIST KW - convulsants KW - Anxiety KW - cerebral ischemia JO - Cerebrovasc.Brain Metab.Rev PY - 1990 AB - 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] RP - NOT IN FILE SP - 1 EP - 26 VL - 2 ER - TY - JOUR AU - Davies,S.N. AU - Collingridge,G.L. TI - Quinoxalinediones as excitatory amino acid antagonists in the vertebrate central nervous system. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Binding,Competitive KW - Glycine KW - pd [pharmacology] KW - Human KW - n-methylaspartate KW - Receptors,N-Methyl-D-Aspartate KW - drug effect KW - ph [physiology] KW - Support,Non-U.S.Gov't KW - Support,U.S.Gov't,P.H.S. KW - up-regulation (physiology) KW - excitatory amino acid antagonists KW - Amino Acids KW - ANTAGONIST KW - central nervous system KW - NERVOUS-SYSTEM KW - SYSTEM JO - Int.Rev Neurobiol. PY - 1990 RP - NOT IN FILE SP - 281 EP - 303 VL - 32 ER - TY - JOUR AU - Fagg,G.E. AU - Olpe,H.R. AU - Schmutz,M. AU - Pozza,M.F. AU - van Riezen,H. AU - Bittiger,H. AU - Angst,C. AU - Brundish,D. AU - Allgeier,H. AU - Heckendorn,R. TI - CGP 37849 and CGP 39551: novel competitive N-methyl-D-aspartate receptor antagonists with potent oral anticonvulsant activity. [Review] KW - NMDA Receptor KW - review KW - Animal KW - asphyxia neonatorum KW - Drug Therapy KW - Brain KW - drug effect KW - brain damage,chronic KW - pc [prevention & control] KW - cerebral anoxia KW - Dizocilpine Maleate KW - tu [therapeutic use] KW - Female KW - glutamates KW - Antagonists & Inhibitors KW - Human KW - infant,newborn KW - PREGNANCY KW - Receptors,N-Methyl-D-Aspartate KW - epilepsy KW - neuroprotective agents KW - N-Methyl-D-Aspartate Receptors KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - POTENT KW - anticonvulsants JO - Prog.Clin.Biol Res PY - 1990 AB - 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] RP - NOT IN FILE SP - 421 EP - 427 VL - 361 ER - TY - JOUR AU - Ford,L.M. TI - Results of N-methyl-D-aspartate antagonists in perinatal cerebral asphyxia therapy. [Review] KW - NMDA Receptor KW - review KW - Animal KW - aspartic acid KW - Antagonists & Inhibitors KW - Binding,Competitive KW - central nervous system KW - ph [physiology] KW - glutamates KW - Hippocampus KW - drug effect KW - Human KW - kainic acid KW - membrane potentials KW - n-methylaspartate KW - Quinoxalines KW - pd [pharmacology] KW - Rats KW - Receptors,N-Methyl-D-Aspartate KW - receptors,neurotransmitter KW - signal transduction KW - Spinal Cord KW - Structure-Activity Relationship KW - Support,Non-U.S.Gov't KW - vertebrates KW - ANTAGONIST JO - Pediatr.Neurol. PY - 1990 RP - NOT IN FILE SP - 363 EP - 366 VL - 6 ER - TY - JOUR AU - Foster,A.C. AU - Gill,R. AU - Iversen,L.L. AU - Kemp,J.A. AU - Wong,E.H. AU - Woodruff,G.N. TI - Therapeutic potential of NMDA receptor antagonists as neuroprotective agents. [Review] KW - NMDA Receptor KW - review KW - Animal KW - Extracellular Space KW - me [metabolism] KW - Glycine KW - pd [pharmacology] KW - Kinetics KW - Neurons KW - drug effect KW - Receptors,N-Methyl-D-Aspartate KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST KW - neuroprotective agents JO - Prog.Clin.Biol Res PY - 1990 RP - NOT IN FILE SP - 301 EP - 329 VL - 361 ER - TY - JOUR AU - Willetts,J. AU - Balster,R.L. AU - Leander,J.D. TI - The behavioral pharmacology of NMDA receptor antagonists [see comments]. [Review] KW - NMDA Receptor KW - review KW - Animal KW - brain diseases KW - pc [prevention & control] KW - Receptors,N-Methyl-D-Aspartate KW - Antagonists & Inhibitors KW - Pharmacology KW - RECEPTORS KW - RECEPTOR ANTAGONIST KW - ANTAGONIST JO - Trends Pharmacol Sci PY - 1990 RP - NOT IN FILE SP - 423 EP - 428 VL - 11 ER -