Abnormal Excitatory Neurotransmitter Metabolism in Schizophrenic Brains

Tsai, Guochuan E.; Passani, Lucius A.; Slusher, Barbara S.; Carter, Ruth; Baer, Lee; Kleinman, Joel E.; Coyle, Joseph T.

doi:10.1001/archpsyc.1995.03950220039008

Cited by 425 publications

(196 citation statements)

References 40 publications

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“…Interestingly, Tsai et al (1995) described increased levels of N-acetylaspartylglutamate (NAAG) in schizophrenic brains. This observation is particularly relevant to the present study, as NAAG is an agonist at mGlu3 receptors (Wroblewska et al, 1997(Wroblewska et al, , 1998.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

Berckel

Kegeles

Waterhouse

et al. 2005

Neuropsychopharmacol

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Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D 2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine-(0.5 mg/kg intravenously (i.v.)) induced decrease in [ 11 C]raclopride equilibrium-specific binding (V 3 00 ) was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [ 11 C]raclopride V 3 00 by 2877% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [ 11 C]raclopride V 3 00 was significantly enhanced (3577%, p ¼ 0.002). The enhancement of the amphetamine-induced reduction in [ 11 C]raclopride V 3 00 by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [ 11 C]raclopride V 3 00 . In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission. Neuropsychopharmacology (2006) 31, 967-977.

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Section: Discussionmentioning

confidence: 99%

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

Berckel

Kegeles

Waterhouse

et al. 2005

Neuropsychopharmacol

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“…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.…”

mentioning

confidence: 93%

“…2 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).…”

mentioning

confidence: 98%

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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“…Proton magnetic resonance spectroscopy ( 1 H MRS) poses an unprecedented opportunity for noninvasive assessment of brain metabolism in well-defined brain areas. N-acetylaspartate (NAA), an amino acid synthesized primarily in neurons (Simmons et al, 1991) and detectable by MRS, can be used as an indirect measure of neuron functionality (Sager et al, 2001;Tsai et al, 1995). Moreover, mature oligodentrocytes can express NAA in vitro (Bhakoo and Pearce, 2000) and it was suggested that glia cells are also involved in NAA/NAAG metabolism.…”

Section: Introductionmentioning

confidence: 99%

Neurotrophic Effects of Electroconvulsive Therapy: A Proton Magnetic Resonance Study of the Left Amygdalar Region in Patients with Treatment-Resistant Depression

Michael

Erfurth

Ohrmann

et al. 2002

Neuropsychopharmacol

185

115

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Negatively balanced neurotrophic factors may be important in precipitating clinical depression. Recently, it has been reported that antidepressant therapy may exert positive neurotrophic effects. The aim of this study was to detect probable neurotrophic changes during electroconvulsive therapy (ECT). For this purpose, N-acetylaspartate (NAA), an amino acid exclusively located in neurons, and other brain metabolites such as glutamine/glutamate (Glx), choline (Cho), and creatine (Cr) were measured in patients by localized proton magnetic resonance spectroscopy. A total of 28 severely depressed patients (DSM-IV) were enrolled, and the left amygdalar region was investigated by proton STEAM spectroscopy before and after unilateral ECT. The results were compared with 28 age-and gender-matched controls using nonparametric paired and unpaired tests. A significant increase in NAA was observed only in ECT responders (n ¼ 14; p ¼ 0.019). Five out of 14 nonresponders to ECT monotherapy were remeasured following a clinical improvement after continued ECT combined with antidepressants and were then found also to present a significant increase in NAA. In all successfully treated patients, parallel observations, that is, increased levels, were made for Glx, whereas Cho and Cr were unchanged. In conclusion, our preliminary finding of increased NAA concentrations after successful ECT may indicate a probable neurotrophic effect of ECT. Neuropsychopharmacology (2003) 28, 720-725.

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Abnormal Excitatory Neurotransmitter Metabolism in Schizophrenic Brains

Cited by 425 publications

References 40 publications

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

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

Neurotrophic Effects of Electroconvulsive Therapy: A Proton Magnetic Resonance Study of the Left Amygdalar Region in Patients with Treatment-Resistant Depression

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