The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior.
TL;DR: The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist, which reduced neuroleptic-induced catalepsy and locomotion.
Abstract: The effects of competitive (CGP 37849 and CGP 39551) and non-competitive (dizocilpine) N-methyl-D-aspartate (NMDA) antagonists were tested in three animal models (catalepsy, sniffing, locomotion) and, in addition, the modulation of these effects by an agonist of the strychnine-insensitive glycine binding site was investigated. Both competitive and non-competitive NMDA antagonists reduced neuroleptic-induced catalepsy. Weak sniffing was induced by the competitive antagonist but strong sniffing by the non-competitive NMDA antagonist. Due to muscle relaxation the competitive antagonist reduced locomotion, in contrast to stimulation of locomotor activity induced by the non-competitive NMDA antagonist. The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist.
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TL;DR: The results indicate that the reversible atrophy induced by 21 days of daily restraint stress requires corticosterone secretion and that excitatory mechanisms involving N-methyl-D-aspartate receptors play a major role in driving the atrophy.
863 citations
Journal Article•
TL;DR: It is shown that glycine enhances electrophysiological responses mediated by N-methyl-d-aspartate (NMDA)b-sensitive glutamatergic receptors through its role as a “spatially aggregating substance” to NMDA receptors.
Abstract: Since the finding by [Johnson and Ascher (1987)][1] demonstrating that glycine enhances electrophysiological responses mediated by N-methyl-d-aspartate (NMDA)b-sensitive glutamatergic receptors, considerable interest has been devoted to this topic (for reviews, see [Dingledine et al. , 1990][2]; [
646 citations
Journal Article•
TL;DR: MK-801-induced behavior represents a rat excitatory amino acid hypofunction model of psychosis that appears to be of clinical relevance and may be of value in the search for new antipsychotic agents.
Abstract: The objective of this study was to characterize the behavior induced by the N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine maleate) in rats as a model of psychosis. The temporal profile, dose dependence, age, and sex differences of the behavior are described. A gas chromatographic method for the analysis of MK-801 in plasma and brain was developed. Female rats showed 4 to 10 times more MK-801-induced behavior and displayed around 25 times higher serum and brain concentrations of MK-801 than male rats. Twenty-one neuroactive compounds, including a number of excitatory amino acid-active substances, were tested for the effect on MK-801-induced behavior. Neuroleptics blocked MK-801-induced behavior in a dose-dependent manner that correlated to their antipsychotic potency in humans. Adenosine receptor agonists and an N-methyl-D-aspartate receptor-associated glycine site antagonist showed putative antipsychotic effects. In conclusion, MK-801-induced behavior represents a rat excitatory amino acid hypofunction model of psychosis that appears to be of clinical relevance and may be of value in the search for new antipsychotic agents.
232 citations
TL;DR: Glutamate receptors represent exciting targets for the development of novel pharmacological therapies for PD as modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy.
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD.
228 citations
TL;DR: A complex interplay between NMDA and opioid receptors is suggested, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability ofNMDA antagonists to elicit sensitization to their own locomotor stimulatory effects.
Abstract: Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 rng/kg) and horizontal locomotion at higher- doses, (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects. © 1994 Wiley-Liss, Inc.
145 citations
References
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TL;DR: G glycine may facilitate excitatory transmission in the brain through an allosteric activation of the NMDA receptor, and can be observed in outside-out patches as an increase in the frequency of opening of the channels activated by NMDA agonists.
Abstract: Transmitters mediating 'fast' synaptic processes in the vertebrate central nervous system are commonly placed in two separate categories that are believed to exhibit no interaction at the receptor level. The 'inhibitory transmitters' (such as glycine and GABA) are considered to act only on receptors mediating a chloride conductance increase, whereas 'excitatory transmitters' (such as L-glutamate) are considered to activate receptors mediating a cationic conductance increase. The best known excitatory receptor is that specifically activated by N-methyl-D-aspartate (NMDA) which has recently been characterized at the single channel level. The response activated by NMDA agonists is unique in that it exhibits a voltage-dependent Mg block. We report here that this response exhibits another remarkable property: it is dramatically potentiated by glycine. This potentiation is not mediated by the inhibitory strychnine-sensitive glycine receptor, and is detected at a glycine concentration as low as 10 nM. The potentiation can be observed in outside-out patches as an increase in the frequency of opening of the channels activated by NMDA agonists. Thus, in addition to its role as an inhibitory transmitter, glycine may facilitate excitatory transmission in the brain through an allosteric activation of the NMDA receptor.
3,018 citations
"The contribution of the different b..." refers background in this paper
...Electrophysiological and binding studies indicate that glycine potentiates the response evoked by NMDA (Johnson and Ascher, 1987)....
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...in electrophysiological experiments (Johnson and Ascher, 1987; Wong et al., 1987)....
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TL;DR: 'The following abbreviations have been used in the text'; I3-N-uxalyl-L-a,l3diaminu-prupiunic acid; ACPD, Trans-l-aminu-cydupentyl-I,3-dicarbuxylate; AMPA, a aminU-3-hydruxy-5-methyl-isoxazole-4-propionate; AP4, 2-
Abstract: 'The following abbreviations have been used in the text; I3-L-ODAP, I3-N-uxalyl-L-a,l3diaminu-prupiunic acid; ACPD, Trans-l-aminu-cydupentyl-I,3-dicarbuxylate; AMPA, a aminu-3-hydruxy-5-methyl-isoxazole-4-propionate; AP4, 2-amino-4-phosphonobutyrate; AP5, 2-amino-5-phuphonovalerate; ASP, aspartate; CNQX, 6-cyano-7-nitro-quinoxaline-2,3-dione; CPP, 3-(2-earboxypiperazin-4-yl)prupyl-l -phosphate; cyelo-Leu, eydo-Ieucine; DAA, D-a amino-adipate; DGG, y-D-glutamylglycine; DNQX, 6,7-dinitro-quinoxaline-2,3dione; EAA, excitatory amino acids; GABA, gamma-aminu-butyric acid; GDEE, glutamate diethyl ester; GLU, glutamate; GL Y, glycine; HA-966, 3-amino-l-hydroxypyrrolidone-2; lBO, ibotenate; IP, inositol phosphate; KA, kainate; KYN, kynurenate; MK-801, dibenzoeyclohepteneimine; NMDA, N-methyl-D-aspartate; PCP, phencyclidine; QA, quisqualate; SER, serine; SOP, serine O-phosphate; TCP, 1-[1-(2-thienyl)-eyclohexyIJpiperidine
2,226 citations
"The contribution of the different b..." refers background in this paper
..." The tested behavioral variables are modified by interfering with the different binding sites of the NMDA receptor, as predicted by a recent receptor model (Foster and Fagg, 1984; Reynolds and Miller, 1988; Monaghan et al., 1989)....
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...Recently, it was reported that D-cycloserine produces an enhancement of acquisition in some learning models (Monaghan et al., 1989), but failed to affect spontaneous locomotion activity or variable interval self-stimulation response rate (Herberg and Rose, 1990)....
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TL;DR: Recovery of behavioural effects correlated with an increase in the remaining levels of DA in the NAS, and there is evidence that remaining DA levels in theNAS are greater at 90 than at 14 days postoperatively.
1,773 citations
"The contribution of the different b..." refers background in this paper
...This dissociates it from the stereotypy induced by dopamine agonists (Kelly et al., 1975)....
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TL;DR: In voltage-clamped oocytes, neither perfusion nor rapid pressure application of NMDA onto messenger RNA-injected oocytes caused a distinct ionic current without added glycine, but when glycine was added, NMDA evoked large inward currents.
Abstract: Receptors for N-methyl-D-aspartate (NMDA) are involved in many plastic and pathological processes in the brain. Glycine has been reported to potentiate NMDA responses in neurons and in Xenopus oocytes injected with rat brain messenger RNA. Glycine is now shown to be absolutely required for activation of NMDA receptors in oocytes. In voltage-clamped oocytes, neither perfusion nor rapid pressure application of NMDA onto messenger RNA-injected oocytes caused a distinct ionic current without added glycine. When glycine was added, however, NMDA evoked large inward currents. The concentration of glycine required to produce a half-maximal response was 670 nanomolar, and the glycine dose-response curve extrapolated to zero in the absence of glycine. Several analogs of glycine could substitute for glycine, among which D-serine and D-alanine were the most effective. The observation that D-amino acids are effective will be important in developing drugs targeted at the glycine site.
1,416 citations
"The contribution of the different b..." refers background in this paper
...Thus glycine is a prerequisite for the activation of the NMDA receptor (Bonhaus et al., 1987; Reynolds et al., 1987; Wong et al., 1987; Kleckner and Dingledine, 1988) and may function as a cotransmitter....
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TL;DR: The distribution of NMDA-sensitive L-[3H]glutamate-binding sites suggests that the NMDA receptor represents a major, distinct subset of excitatory amino acid receptors and indicates regions in which neurotransmission may be mediated or modulated by this receptor.
Abstract: N-methyl-D-aspartate (NMDA) is an acidic amino acid which depolarizes neurons by selectively interacting with a distinct class of excitatory amino acid receptor. Recent evidence has indicated that this receptor is a neurotransmitter receptor in the spinal cord, cerebral cortex, and hippocampus for which the endogenous ligand is likely to be L-glutamate or a structurally related compound. Using quantitative autoradiography, we have studied the anatomical distribution of the class of L- [3H]glutamate-binding sites displaced by NMDA, which appear to correspond to NMDA receptors. The CA1 region of the hippocampus contains the highest density of sites. In general, telencephalic regions have high levels of binding sites. The cerebral cortex shows significant density variations among the differing layers and regions, with the highest levels found in the frontal cortex layers I to III. Within the basal ganglia, the highest levels are found in the nucleus accumbens, intermediate levels are found in the caudate/putamen, and very low levels are found in the globus pallidus. Thalamic regions have moderate levels with variations among differing regions. Midbrain and brainstem have low levels of binding sites, but within these regions there are structures exhibiting higher levels, e.g., the nucleus of the solitary tract and the inferior olive. The distribution of NMDA sites is consistent with most, but not all, of the regions previously proposed to use glutamate as an excitatory transmitter. Thus, the distribution of NMDA-sensitive L-[3H]glutamate-binding sites suggests that the NMDA receptor represents a major, distinct subset of excitatory amino acid receptors and indicates regions in which neurotransmission may be mediated or modulated by this receptor.
1,307 citations
"The contribution of the different b..." refers background in this paper
...Modulatory sites are: a strychnine-insensitive glycine binding site, nearly identically distributed as the NMDA binding site ( Monaghan and Cotman, 1985; Bristow et al., 1986); a polyamine...
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...The N-methyl-D-aspartate receptor (NMDA), one subtype of excitatory amino acid receptors is fairly well described in its regional distribution in the brain (Monaghan et al., 1983; Monaghan and Cotman, 1985 )....
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