d-Cycloserine: A ligand for the coupled glycine receptor has partial agonist characteristics

Hood, William F.; Compton, Robert P.; Monahan, Joseph B.

doi:10.1016/0304-3940(89)90379-0

Cited by 292 publications

(147 citation statements)

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“…However, it functions as only a partial agonist, producing only 40-60% of the response seen with either glycine or D-serine. 25 Attempts to modify glycine or D-serine to produce synthetic glycine-site agonists have, so far, been unsuccessful. Thus, aside from the use of glycine or D-serine, indirect approaches must be taken to activate NMDAR via the glycine site.…”

Section: Modulatory Sitesmentioning

confidence: 99%

“…99 D-Cycloserine functions as a glycine site agonist in the presence of high glycine concentrations, and as an antagonist in the presence of high concentrations. 25 A parsimonious explanation for the D-cycloserine induced worsening of symptoms, therefore, is that clozapine may already increase synaptic glycine levels through as yet unknown mechanisms. Recently, clozapine has recently been shown to block glycine and glutamine transport mediated by SNAT2-like synaptosomal transporters, providing a potential mechanism for both the differential therapeutic effects of clozapine and the differential effects of NMDAR modulators in the presence of clozapine vs other antipsychotics.…”

Section: Glutamatergicmentioning

confidence: 99%

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Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Modulatory Sitesmentioning

confidence: 99%

Section: Glutamatergicmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…Following the observation that the noncompetitive NMDA receptor antagonist PCP can induce a psychotomimetic state akin to schizophrenia (Javitt & Zukin, 1991), it was proposed that facilitation of NMDA receptor function might provide a therapeutic benefit in schizophrenia. Thus, agonists at the glycine site of the NMDA receptor, such as glycine, serine, or d-cycloserine (Henderson et al, 1990;Hood et al, 1989;Watson et al, 1990), have been tested in clinical studies and have shown promise as adjuvants in the treatment of schizophrenia (Dall'Olio & Gandolfi, 1993;Goff et al, 1995bGoff et al, , 1999bHeresco-Levy et al, 1996aJavitt et al, 1994;Tsai et al, 1998b).…”

Section: Pharmacology Of Glutamate Receptorsmentioning

confidence: 99%

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

Konradi

Heckers

2003

Pharmacology & Therapeutics

287

157

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The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.

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“…Thus, its effect on NMDA receptor activity may depend on the occupancy of the glycine binding site by (the endogeneous agonist) glycine: if this recognition site is not fully saturated in vivo, D-cycloserine may be expected to enhance the stimulating effects of the endogeneous glycine in low dosages while in high dosages D-cycloserine could reduce this effect, due to its competition with glycine. Therefore, the effects of D-cycloserine may be biphasic at different doses: agonistic at lower doses and antagonistic at higher doses.Several studies using challenge paradigms found that the systemic administration of 3-20 mg/kg of D-cycloserine in rats exerts an agonistic effect on NMDA receptors using different models, like immediate early genes (Gao et al 1997), second messenger response (Emmett et al 1991), enhancement of TCP binding (Hood et al 1980), facilitation of performance in learning tasks (Monahan et al 1989;Quartermain et al 1994). An agonistic effect of D-cycloserine is also suggested in human subjects using secretion of luteinizing hormone (LH) since preclinical studies indicate that LH secretion increases in response to NMDA receptor stimulation (van Berckel et al 1998b).…”

mentioning

confidence: 99%

“…Several studies using challenge paradigms found that the systemic administration of 3-20 mg/kg of D-cycloserine in rats exerts an agonistic effect on NMDA receptors using different models, like immediate early genes (Gao et al 1997), second messenger response (Emmett et al 1991), enhancement of TCP binding (Hood et al 1980), facilitation of performance in learning tasks (Monahan et al 1989;Quartermain et al 1994). An agonistic effect of D-cycloserine is also suggested in human subjects using secretion of luteinizing hormone (LH) since preclinical studies indicate that LH secretion increases in response to NMDA receptor stimulation (van Berckel et al 1998b).…”

mentioning

confidence: 99%

D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

Berckel¹

1999

Neuropsychopharmacology

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A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine (Paschen 1996) and schizophrenia (Javitt and Zukin 1991;Henn 1995;Olney and Farber 1995).In schizophrenia, a role for excitatory amino acids and NMDA receptors was suggested when NMDA receptor antagonists, such as phencyclidine (PCP) and ketamine, were found to induce symptoms resembling the positive and negative symptoms of schizophrenia in healthy subjects and exacerbate such symptoms in patients with schizophrenia (Luby et al. 1962;Javitt and Zukin 1991;Krystal et al. 1994;Lahti et al. 1995;Malhotra et al. 1997b). A hypofunction of the glutamatergic system and NMDA receptors has been hypothesized in schizophrenia (for review, see Olney and Farber 1995) and appears to be supported by post-mortem studies (Nishikawa et al. 1983;Toru et al. 1988;Ishimaru et al. 1994;Tsai et al. 1995). If schizophrenic symptoms are the result of the diminished functioning of NMDA receptors, stimulation of these receptors could be beneficial for patients with schizophrenia. Glycine and D-cycloserine stimulate the strychnine-insensitive glycine recognition site of the NMDA receptor and, by inference, may ameliorate schizophrenic symptoms. Some studies have used glycine for this purpose. In a double-blind, parallel, placebo-controlled study with seven patients in each group, glycine treatment during 8 weeks in a dose ‫ف‬ 30 grams daily, added to typical antipsychotics, selectively reduced the scores on the negative symptom subscale of the Positive and Negative Symptoms Scale (PANSS) (Javitt et al. 1994). A similar result has also been reported in 11 schizophrenic patients using glycine in dosages between 40 and 80 grams daily in a doubleblind crossover design with treatment periods of 6 weeks (Heresco-Levy et al. 1996). These two studies suggest that stimulation of the NMDA receptor may ameliorate the negative symptoms of schizophrenia.As a treatment of schizophrenic symptoms, glycine's major limitation is its limited access to the central nervous system (CNS). Contrary to glycine, the partial NMDA agonist D-cycloserine, an antibiotic used in the treatment of tuberculosis (Walker and Murdoch 1957), rapidly passes the blood-brain barrier and may therefore be more suitable for the treatment of patients with schizophrenia than glycine. However, D-cycloserine acts as a partial agonist of the NMDA receptor, with around 60%-90% of the agonistic efficacy of glycine (Chessell et al. 1991;Priestley et al. 1995) and with between 6 to 20 times less affinity for the glycine recognition site of the NMDA receptor than glycine (Ishimaru et al. 1994;Priestley et al. 1995)...

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d-Cycloserine: A ligand for the coupled glycine receptor has partial agonist characteristics

Cited by 292 publications

References 10 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

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