Antipsychotic drug effects on glutamatergic activity

Lidsky, T.I.; Yablonsky-Alter, Elena; Zuck, L.; Banerjee, Sipra

doi:10.1016/s0006-8993(97)00423-x

Cited by 45 publications

(23 citation statements)

References 29 publications

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“…These drugs interfere with NMDA-mediated neurotransmission. Indeed, in clinically effective concentrations, haloperidol can stimulate NMDA receptors (Banerjee et al 1995), as can chlorpromazine and thioridazine (Lidsky et al 1997). Moreover, data from electrophysiological studies, using whole cell voltage clamp in cultured hippocampal neurons suggest that haloperidol may act as a partial agonist at the glycine recognition site of the NMDA receptor (Fletcher and Macdonald 1993).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…This has led to the hypothesis that schizophrenia is caused by an overactive dopaminergic system (Meltzer & Stahl, 1976). However, conventional antipsychotic drugs are not just D 2 antagonists, but are also effectors of other neurotransmitter systems (Andersson et al, 1998;Stockmeier et al, 1993) and, to some part, of the glutamate system (see Section 3.3) (Arvanov et al, 1997;Brimecombe et al, 1998;Fletcher & MacDonald, 1993;Gallagher et al, 1998;Ilyin et al, 1996;Lidsky et al, 1997;Micheletti et al, 1993).…”

Section: Pharmacology Of Antipsychotic Drugsmentioning

confidence: 99%

“…Interestingly, many of the known antipsychotic drugs interact directly with the glutamate system. At concentrations similar to those found in the cerebrospinal fluid of schizophrenics, antipsychotic drugs bind to NMDA receptors, augment NMDA activity, and increase the expression of AMPA and NMDA receptor subtypes (Banerjee et al, 1995;Brene et al, 1998;Eastwood et al, 1996;Fitzgerald et al, 1995;Lidsky et al, 1997;Meshul et al, 1996). Chronic treatment with conventional antipsychotic drugs inhibits the glutamate transporter (De Souza et al, 1999) and increases the basal concentration of extracellular glutamate (Meshul et al, 1996;Yamamoto & Cooperman, 1994).…”

Section: Direct Interaction Of Antipsychotic Drugs With the Glutamatementioning

confidence: 99%

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

Konradi

Heckers

2003

Pharmacology & Therapeutics

294

165

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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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“…Nevertheless, it has antiserotoninergic, anti-muscarinic, antihistaminergic and α-adrenergic receptor inhibitory activity as well ( Figure 4). N-Methyl-D-aspartate (NMDA) receptor inhibitory effects have also been described at high concentrations of chlorpromazine (19).…”

Section: Principal Compounds With Phenothiazine Skeleton and Their Stmentioning

confidence: 99%

“…It has recently been reported that at low concentration, phenothiazine derivatives stimulate glutaminergic transmission on NMDA receptors, and at high concentration, they inhibit it (19).…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Possible Biological and Clinical Applications of Phenothiazines

Varga

Csonka

et al. 2017

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Abstract. Phenothiazines have been used in many areasPhenothiazines are unanimously one of the most versatile compounds from the view of biological activity. Since their discovery, new exploitable pharmacological properties have emerged from time to time; thus, they have an important role in many areas of medicine and beyond. This is why phenothiazines are basic compounds in pharmacology. The history of these compounds goes back to the second half of the 19th century, when a German chemist, Heinrich August Bernthsen began to study the structure of methylene blue, which was first synthesized in 1876 by Heinrich Caro. In 1885, two years after Bernthsen first managed to produce phenothiazine, he also succeeded in describing the structure of methylene blue (1). At the same time, Paul Ehrlich began to investigate the possible therapeutic use of methylene blue in malaria infections, which he first published in 1891 (2). Due to this, methylene blue was often prescribed for patients with malaria in the subsequent period (3).Research conducted in the 1930s and '40s proved the potential wide use of phenothiazines. The insecticidal (4), antihelmintic (5, 6), and antibacterial (7) effects of the compound were detected; however, it was not widely used for these purposes. In the 1940s, another novel phenothiazine derivative, namely promethazine was brought to the forefront of attention; it was investigated by Paul Charpentier at the Rhone-Poulenc laboratory in Paris (8). It was shown that promethazine had an antihistamine effect (9), which was later used in the therapy of allergic diseases and in anesthesia (10,11). A few years later in the same laboratory, chlorpromazine was discovered, which has strong anxiolytic and antipsychotic effect along with its antihistaminic effect (12). Psychiatry fully exploited this feature in psychotic patients (13), which resulted in the almost complete emptying of psychiatric hospitals in the 1950s. As a result, the discovery of chlorpromazine and the beginning of its use as an antipsychotic are considered the beginning of modern psychiatry and psychopharmacology.Since then, several antipsychotic phenothiazine compounds have been used in clinical practice, although research conducted in the last couple of decades indicated that phenothiazine compounds could have an important role in other fields of medicine as well, such as in the treatment of tumorous, infectious, or neurodegenerative diseases (3). 5983

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Antipsychotic drug effects on glutamatergic activity

Cited by 45 publications

References 29 publications

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

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

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

Possible Biological and Clinical Applications of Phenothiazines

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