Strychnine-insensitive Glycine Receptor Research Articles

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups

Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4′-fluorophenyl)-3(4′-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors.

1-aminocyclopropanecarboxylic acid (ACPC) produces procognitive but not antipsychotic-like effects in rats.

RationaleIn addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-aminocyclopropanecarboxylic acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors.ObjectivesWe investigated the procognitive and antipsychotic-like effects of ACPC in rats treated with phencyclidine (PCP) or ketamine (KET), compounds that produce psychotic-like symptoms in humans and laboratory animals.MethodsCognitive effects were investigated in the novel object recognition (NOR) and attentional set-shifting tests (ASST). In addition, the effects of ACPC were investigated in PCP-induced hyperactivity, conditioned avoidance response (CAR), and prepulse inhibition (PPI) tests. The effects on attention and impulsivity were measured in the five-choice serial reaction time task (5-CSRTT).ResultsACPC (200–400 mg/kg) inhibited memory fading in naive rats and like clozapine prevented PCP- and KET-induced amnesia in the NOR. In naive animals, ACPC at 400 but not 200 mg/kg enhanced cognitive flexibility in the ASST, as the animals required fewer trials to reach the criteria during the extra-dimensional phase. In contrast, ACPC did not affect PCP-induced hyperactivity, CAR, and PPI as well as attention and impulsivity in the 5-CSRTT.ConclusionThe present study demonstrates that ACPC enhanced both object recognition memory and cognitive flexibility dependent on the prefrontal cortex, but did not affect impulsivity nor exhibit an antipsychotic-like profile.

ChemInform Abstract: Novel Indole-2-carboxylates as Ligands for the Strychnine-Insensitive N-Methyl-D-aspartate-Linked Glycine Receptor.

A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex. All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor. The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 microM vs [3H]glycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex. These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor. The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands. In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.

Antinociceptive effects of systemic lidocaine: Involvement of the spinal glycinergic system

Beside their action on voltage-gated Na + channels, local anesthetics are known to exert a variety of effects via alternative mechanisms. The antinociceptive effect of lidocaine is well documented, yet the exact mechanism is not fully understood. Whether glycinergic mechanisms, which play a pivotal role in pain modulation, are involved in lidocaine-induced antinociception is hitherto unclear. In the present study, lidocaine was injected intravenously in rats using the formalin test for acute pain and the chronic constriction injury model for neuropathic pain. The effect of intrathecally administered d-serine (an agonist at the glycine-binding site at the NMDA-receptor), its inactive isomer l-serine, CGP 78608 (antagonist at the glycineB-site of the NMDA-receptor) and strychnine (antagonist at inhibitory glycine-receptors) on lidocaine-induced antinociception was examined. Systemically administered lidocaine was antinociceptive in both acute and chronic pain model. In the formalin test, the effect of lidocaine was antagonized by d-serine, but not by l-serine or strychnine. In the chronic constriction injury model, antinociception evoked by lidocaine was reduced by d-serine, strychnine and CGP 78608, while l-serine had no effect. These results indicate a modulatory effect of lidocaine on the NMDA-receptor. Additionally, since in our study lidocaine-induced antinociception was antagonized by both glycineB-site modulators and strychnine our results may favor the hypothesis of a general glycine-like action of lidocaine or some of its metabolites on inhibitory strychnine-sensitive receptors and on strychnine-insensitive glycine receptors.

P.3.d.011 In vitro and in vivo characterization of glycine transporter type-1 by two inhibitors, Org-24461 and NFPS

Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4′-fluorophenyl)-3(4′-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors.

Taurine and the control of basal hormone release from rat neurohypophysis

Pituicytes of pituitary neural lobe are rich in the amino acid taurine, which they release upon hypoosmotic stimulation. As a generally inhibitory amino acid, taurine is thought to activate receptors on neural lobe nerve terminals and exert some control over hormone release. Previous work has shown the presence of glycine and GABA A receptors in neural lobe, both of which have affinity for taurine. Using a perifused explant system, we studied the effects of taurine activation of glycine and GABA A receptors on basal hormone release. Somewhat surprisingly, taurine induced increases in basal release of both vasopressin and oxytocin. Taurine-induced increases in oxytocin release were blocked by bicuculline, suggesting involvement of GABA A receptors. Increases in vasopressin release were not blocked by bicuculline, indicating involvement of receptors other than GABA A. Although combined bicuculline and strychnine, an antagonist at most glycine receptors, also did not block increased vasopressin release, picrotoxin (a Cl − channel blocker) was effective in blocking increases in both vasopressin and oxytocin release. The other receptor(s) involved in taurine actions is postulated to be strychnine-insensitive glycine receptors. Thus, taurine in neural lobe may act via both a GABA A receptor and one or more types of glycine receptors to depolarize nerve terminal membranes under basal conditions. Taurine-induced partial depolarization resulting in Na + channel inactivation is probably responsible for its previously observed inhibition of stimulated hormone release from neural lobe.

Selective Blockade of Drug-induced Place Preference Conditioning by ACPC, a Functional NDMA-receptor Antagonist

ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some clinical utility in the treatment of addiction, without affecting responses to natural rewards.

A Self‐Complementary, Self‐Assembling Microsphere System: Application for Intravenous Delivery of the Antiepileptic and Neuroprotectant Compound Felbamate

Felbamate (FBM) is a novel antiepileptic drug (AED) and neuroprotectant (NP) compound that interacts with strychnine‐insensitive (SI) glycine receptors in brain (IC50 = 374 μM). FBM concentrations required to interact with SI glycine receptors are consistent with brain levels following oral and intraperitoneal administration of AED and NP doses. Because of the solubility limits of FBM, an intravenous (iv) form has not been developed. Nevertheless, an iv form could be important for the treatment of disorders such as status epilepticus and neuronal damage due to hypoxic/ischemic events. Substituted diketopiperazines precipitate in acid to form microspherical particles of uniform size (∼2 μm). The microsphere system entraps drugs on precipitation and dissolves near physiological pH to release the drug cargo. Therefore, microspheres were used to produce an iv formulation of FBM. Mice were administered the FBM/microsphere (20–60 mg/kg FBM) and tested for protection against tonic extension seizures using maximal electroshock. The FBM/microsphere was effective in a time‐ and dose‐dependent manner following iv administration. The median effective dose (ED50) for protection against MES seizures at 30 min was 27.2 mg/kg [95% confidence interval (CI) = 20.8–33.4, slope = 6.5]. The ED50 for minimal motor impairment at 30 min was 167 mg/kg (95% CI = 155–177, slope = 28.1). Thus, the feasibility of encapsulating FBM or similar aqueous insoluble compounds in a microsphere system with delivery by the iv route for treatment of epilepsy and various central nervous system disorders has been clearly demonstrated. Studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals. © Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89:867–875, 2000

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EpilepsiaVolume 41, Issue 7 p. 918-919 Free Access REPLY Claude G. Wasterlain, Claude G. Wasterlain Department of Neurology, UCLA School of Medicine, VA Medical Center, Sepulveda, California, U.S.A.Search for more papers by this authorAndrey M. Mazarati, Andrey M. Mazarati Department of Neurology, UCLA School of Medicine, VA Medical Center, Sepulveda, California, U.S.A.Search for more papers by this author Claude G. Wasterlain, Claude G. Wasterlain Department of Neurology, UCLA School of Medicine, VA Medical Center, Sepulveda, California, U.S.A.Search for more papers by this authorAndrey M. Mazarati, Andrey M. Mazarati Department of Neurology, UCLA School of Medicine, VA Medical Center, Sepulveda, California, U.S.A.Search for more papers by this author First published: 02 August 2005 https://doi.org/10.1111/j.1528-1157.2000.tb00266.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. REFERENCES 1 McCabe RT, Sofia RD, Layer RT, Leiner KA, Faull RLM, Narang N, Walmsley JK. Felbamate increases [3H]glycine binding in rat brain and sections of human postmortem brain, J Pharmacol Exp Ther 1998; 286: 991– 999. 2 Wallis RA, Panizzon KL. Glycine reversal of felbamate hypoxic protection. Neuroreport 1993; 4: 951– 954. 3 White HS, Harmsworth WL, Sofia RD, Wolf HH. Felbamate modulates the strychnine-insensitive glycine receptor. Epilepsy Res 1995; 20: 41– 48. 4 Kanthasamy AG, Matsumoto RR, Gunasekar PG, Trunong DD. Excitoprotective effect of felbamate in cultured cortical neurons. Brain Res 1995; 705: 97– 104. 5 Taylor LA, McQuade RD, Tice MA. Felbamate, a novel antiepileptic drug, reverses N-methyl-D-aspartate/glycine-stimulated increases in intracellular Ca2+ concentration, Eur J Pharmacol Mol Pharmacol 1995; 289: 229– 233. 6 Kleckner NW, Glazewski JC, Chen CC, Moscrip TD. Subtype-selective antagonism of N-methyl-D-aspartate receptors by felbamate: insights into the mechanism of action, J Pharmacol Exp Ther 1999; 289: 886– 894. 7 Harty TP, Rogawski MA. Felbamate block of recombinant N-methyl-D-aspartate receptors: selectivity for the NR2B subunit, Epilepsy Res 2000; 39: 47– 55. 8 Subramaniam S, Rho JM, Penix L, Donevan SD, Fielding RP, Rogawski MA. Felbamate block of the N-methyl-D-aspartate receptor, J Pharmacol Exp Ther 1995; 273: 878– 886. Volume41, Issue7July 2000Pages 918-919 ReferencesRelatedInformation

Beneficial Effects of Glycine (Bioglycin) on Memory and Attention in Young and Middle-Aged Adults

The N-methyl D-aspartate receptor complex is involved in the mechanism of long-term potentiation, which is thought to be the biological basis of learning and memory. This complex can be manipulated in a number of ways, one of which is through the strychnine-insensitive glycine receptor coagonist site. The effects of Bioglycin(Konapharma, Pratteln, Switzerland), a biologically active form of the amino acid glycine, were therefore studied in healthy students (mean age, 20.7 years) and middle-aged men (mean age, 58.9 years) with tests that measured attention, memory and mood, using a double-blind, randomized, crossover design. Compared with the young group, the middle-aged group had significantly poorer verbal episodic memory, focused, divided, and sustained attention; they also differed in their subjective responses at the end of testing. Bioglycin significantly improved retrieval from episodic memory in both the young and the middle-aged groups, but it did not affect focused or divided attention. However, the middle-aged men significantly benefited from Bioglycin in the sustained-attention task. The effects of Bioglycin differed from those of other cognitive enhancers in that it was without stimulant properties or significant effects on mood, and it primarily improved memory rather than attention. It is likely to be of benefit in young or older people in situations where high retrieval of information is needed or when performance is impaired by jet lag, shift work, or disrupted sleep. It may also benefit the impaired retrieval shown in patients with schizophrenia, Parkinson's disease, and Huntington's disease.

Design, synthesis and structure-activity relationships of novel strychnine-insensitive glycine receptor ligands

The in vitro activities of 3-hydroxy-imidazolidin-4-one derivatives demonstrated very restricted structure-activity relationships at the strychnine-insensitive glycine site of the NMDA receptor. The most active compound ( 3a) was completely unsubstituted and exhibited affinity and efficacy similar to that of D-cycloserine, the prototypical partial agonist at this site.

ACPC, a partial agonist at strychnine-insensitive glycine receptors, has no effect on the discriminative stimuli of amphetamineand cocainea

ACPC, a partial agonist at strychnine-insensitive glycine receptors, has no effect on the discriminative stimuli of amphetamineand cocainea

Strychnine-insensitive [3H] glycine binding to synaptosomal membranes from the chick retina

The pharmacology and kinetics of strychnine-insensitive [[3]H] glycine binding to synaptic membranes from the outer (P1) and the inner (P2) plexiform layers of chick retina was studied. Inhibition curves for glycine, d-serine, 1-amincyclopropanecarboxylic acid (ACPC) and strychnine were analyzed by non-linear regression. Hill slopes for glycine and d-serine were not different from unity, whereas those for ACPC were < 1 in both fractions, revealing heterogeneity of binding sites in these membranes. Non-linear regression analysis of time course and saturation experiments strengthen the idea that [[3]H] glycine binds to more than one class of sites, with similar affinities at equilibrium. Antagonists of strychnine-insensitive glycine receptors in the CNS did not inhibit [[3]H] glycine binding to these membranes, which demonstrates that NMDA receptors in the retina have different structural requirements for ligand interaction at these sites. pH affected the specific binding, in agreement with the participation of specific amino acid residues at glycine binding sites on NMDA receptors, and also with functional studies in which the modulation of affinity at this site by protons has been observed. These results support previous studies regarding CPP and MK-801 binding, and provide evidence which indicates that the pharmacophore for glycine and other NMDA-related ligands is distinct for the retina, compared to the CNS, mainly regarding the effects of glycine-site antagonists.

Anxiolytic- and antidepressant-like effects of L-701,324, an antagonist at strychnine-insensitive glycine receptors: E. Tatarczyńska, E. Chojnacka-Wójcik, E. Przegaliński. Institute of Pharmacology, Polish Academy of Sciences, 12 Sm [formula omitted]tna Street, 31-343 Kraków, Poland

Anxiolytic- and antidepressant-like effects of L-701,324, an antagonist at strychnine-insensitive glycine receptors: E. Tatarczyńska, E. Chojnacka-Wójcik, E. Przegaliński. Institute of Pharmacology, Polish Academy of Sciences, 12 Sm [formula omitted]tna Street, 31-343 Kraków, Poland

Structural and functional properties of erythrocytes in patients with chronic alcoholism under lazer therapy : M.V. Ovsyannikov, T.Yu. Gaidadimova, N.P. Milutina, A.A. Ananyan, V.V. Vnukov. The Department of Biochemistry, Rostov State University, B. Sadovaya, 105, 344006. Municipal hospital No 7, Profsoyuznaya, 49, 344001, Rostov-on-Don, Russia

The pharmacology and kinetics of strychnine-insensitive [[3]H] glycine binding to synaptic membranes from the outer (P1) and the inner (P2) plexiform layers of chick retina was studied. Inhibition curves for glycine, d-serine, 1-amincyclopropanecarboxylic acid (ACPC) and strychnine were analyzed by non-linear regression. Hill slopes for glycine and d-serine were not different from unity, whereas those for ACPC were < 1 in both fractions, revealing heterogeneity of binding sites in these membranes. Non-linear regression analysis of time course and saturation experiments strengthen the idea that [[3]H] glycine binds to more than one class of sites, with similar affinities at equilibrium. Antagonists of strychnine-insensitive glycine receptors in the CNS did not inhibit [[3]H] glycine binding to these membranes, which demonstrates that NMDA receptors in the retina have different structural requirements for ligand interaction at these sites. pH affected the specific binding, in agreement with the participation of specific amino acid residues at glycine binding sites on NMDA receptors, and also with functional studies in which the modulation of affinity at this site by protons has been observed. These results support previous studies regarding CPP and MK-801 binding, and provide evidence which indicates that the pharmacophore for glycine and other NMDA-related ligands is distinct for the retina, compared to the CNS, mainly regarding the effects of glycine-site antagonists.

Birth order and gender of heroin addicts: the role of siblings in the addict's “career” : V. Pomini, J. Liappas, V. Peppas, N. Papavasiliou, G. Christodoulou. Athens University Medical School Department of Psychiatry Vas. Sophias 72-1 1528 Athens, Greece

The anticonvulsants diazepam (1–10 mg/kg) and phenobarbital (30–100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor comples, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.

GV 150526A, 7-Cl-kynurenic acid and HA 966 antagonize the glycine enhancement of N-methyl-d-aspartate-induced [[formula omitted]]noradrenaline and [[formula omitted]]dopamine release

The effect of selective antagonists (7-Cl-kynurenic acid, 3-amino-1-hydroxypyrrolid-2-one (HA 966) and GV 150526A) at strychnine-insensitive glycine sites was studied by measuring how much glycine potentiated the [3H]dopamine and [3H]noradrenaline release induced by 100 μM N-methyl-d-aspartate (NMDA) from superfused striatal and hippocampal synaptosomes, respectively, in a Mg2+-free buffer. Glycine, which per se had no effect on [3H]catecholamine release, concentration-dependently potentiated the effect of NMDA, with similar potency in the two brain regions (EC50 0.25 and 0.27 μM for [3H]dopamine and [3H]noradrenaline release, respectively). 7-Cl-Kynurenic acid reduced the effect of NMDA alone and antagonized the effect of 1 μM glycine, with Ki respectively 1.1 and 0.6 μM for [3H]dopamine and [3H]noradrenaline release. HA 966 did not inhibit the effect of NMDA alone, but reduced the effect of glycine with Ki=11.5 and 66 μM for [3H]dopamine and [3H]noradrenaline release. GV150526A inhibited the effect of NMDA alone and potently antagonized the effect of glycine, with Ki=12.4 and 17.3 nM for [3H]dopamine and [3H]noradrenaline release. Our results are consistent with the possibility that HA 966 is a partial agonist, while 7-Cl-kynurenic acid and GV 150526A are competitive antagonists at the strychnine-insensitive glycine sites. In addition HA 966 shows regional differences in its interaction with the strychnine-insensitive glycine receptor, being about six times more potent on striatal than on hippocampal synaptosomes, suggesting a possible heterogeneity of glycine sites recognized by HA 966 or different intrinsic activity in the two brain regions. The nanomolar potency of GV 150526A in reducing NMDA receptor function by competitively acting at the strychnine-insensitive glycine sites suggests that GV 150526A could be effective in vivo to reduce NMDA receptor over-stimulation, like in brain ischemia.

Competitive NMDA and Strychnine-Insensitive Glycine-Site Antagonists Disrupt Prepulse Inhibition

Prepulse inhibition (PPI) is thought to reflect the operation of a sensorimotor gating system in the brain. Sensorimotor gating abnormalities have been identified in schizophrenic patients, and various neural systems are involved in this function. To study the modulation of the sensorimotor gating system by the N-methyl- d-aspartate (NMDA) receptor–channel complex, the effects of noncompetitive and competitive NMDA antagonists on PPI were examined in rats. PPI was not disrupted by CGS 19755, a competitive NMDA antagonist, at 30 min after subcutaneous (SC) administration. However, CGS 19755 (40 mg/kg SC) decreased PPI at 120 min after administration with a marked decrease of startle amplitude. Late onset of the effect of CGS 19755 was also observed in the increase of spontaneous locomotor activity (SLA). On the other hand, phencyclidine, a noncompetitive NMDA antagonist, disrupted PPI at 30 min after administration and increased SLA from 20 min after administration. PPI was also disrupted by bilateral intracerebroventricular administration of 5,7-dichlorokynurenate (10 and 20 μg/side × 2), an antagonist at the strychnine-insensitive glycine receptor, which is an allosteric binding site in the NMDA receptor–channel complex. It is concluded that the NMDA receptor–channel complex plays an important role in regulation of PPI.

Characterization of a novel putative cognition enhancer mediating facilitation of glycine effect on strychnine-resistant sites coupled to NMDA receptor complex

The effects of (S)-4-amino-5-[(4,4-dimethylcyclohexyl)amino]-5-oxo-pentanoic acid ((S)CR 2249), a new chemical entity selected among a series of glutamic acid derivatives, were investigated on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline from rat hippocampal slices. (S)CR 2249 facilitated glycine-mediated reversion of kynurenate antagonism at strychnine-insensitive glycine receptors coupled to the NMDA receptor. The potency of glycine (EC50 = 21.5 microM +/- 4.2) was not significantly influenced by (S)CR 2249. Nevertheless, the efficacy of the glycine effect was enhanced in a concentration-dependent manner (3-10-30 microm) by (S)CR 2249. The interaction of (S)CR 2249 with NMDA receptors was also studied with binding experiments, in which we examined the effect of (S)CR 2249 on the modulation by glutamate, glycine and spermine of [3H]dizocilpine (MK-801) binding. (S)CR 2249, increased [3H]MK-801 binding in a concentration-dependent manner and we found positive cooperative interactions between glycine and (S)CR 2249, indicating that (S)CR 2249 probably acts at a separate allosteric site to increase NMDA receptor functionality.

GABA and epileptogenesis.

GABA and epileptogenesis.