Anti-glutamatergic effects of clozapine

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

doi:10.1016/0304-3940(93)90370-z

Cited by 51 publications

(26 citation statements)

References 17 publications

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“…Another study also reported a trend to reduced NMDA receptor binding in striatum after chronic treatment with clozapine but not with haloperidol (Spurney et al, 1999). This effect of clozapine may result from its proposed antagonistic action at NMDA receptors (Lidsky et al, 1993). However, it is unlikely that the effects of olanzapine, risperidone, or quetiapine result from direct NMDA receptor blockade because the three drugs showed very low affinity for MK-801 binding sites (all K i values Ͼ10 M) based on our in vitro assays.…”

Section: Resultsmentioning

confidence: 95%

Long-Term Effects of Olanzapine, Risperidone, and Quetiapine on Ionotropic Glutamate Receptor Types: Implications for Antipsychotic Drug Treatment

Tarazi¹,

Baldessarini²,

Kula³

et al. 2003

J Pharmacol Exp Ther

114

204

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Levels of ionotropic glutamate (Glu) N-methyl-D-aspartate (NMDA),␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainic acid (KA) receptors in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after continuous treatment for 28 days with the atypical antipsychotics olanzapine, risperidone, and quetiapine, or vehicle controls. All three treatments significantly decreased NMDA binding in caudate-putamen (CPu; by 30, 34, and 26%, respectively) but increased AMPA receptor levels in same region (by 22, 30, and 28%). Olanzapine and risperidone, but not quetiapine, also reduced NMDA receptor labeling in hippocampal CA1 (21 and 19%) and CA3 (23 and 22%) regions. KA receptors were unaltered by any treatment in the brain regions examined. These findings suggest that the antipsychotic effects of olanzapine and risperidone may be mediated in part by NMDA receptors in hippocampus, and perhaps AMPA receptors in CPu. The findings also support the hypothesis that down-regulation of NMDA receptors by atypical antipsychotic agents in CPu contributes to their low risk of extrapyramidal side effects. Inability of olanzapine, risperidone, and quetiapine to alter KA receptors suggests their minimal role in mediating the central nervous system actions of these drugs.

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Section: Resultsmentioning

confidence: 95%

Long-Term Effects of Olanzapine, Risperidone, and Quetiapine on Ionotropic Glutamate Receptor Types: Implications for Antipsychotic Drug Treatment

Tarazi¹,

Baldessarini²,

Kula³

et al. 2003

J Pharmacol Exp Ther

114

204

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“…Electrophysiological studies by Lidsky and colleagues show that CLZ has glutamate antagonistic properties which potentially occur at therapeutic levels (Lidsky et al, 1993). Glutamate receptor antagonism may occur primarily through direct antagonism at the NMDA receptor or secondarily through CLZ's antidopaminergic effects.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, CLZ has been reported to differ from HDL in its effect on glutamate release in the striatum (Yamamoto and Cooperman, 1994). However, both HDL and CLZ can directly displace the binding of tritiated MK-801 from the NMDA receptor (Janowsky and Berger, 1989;Lidsky et al, 1993). The direct effect of CLZ on glutamate receptor density is controversial.…”

Section: Introductionmentioning

confidence: 96%

Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats

Spurney

Baca

Murray

et al. 1999

Synapse

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Despite multiple lines of investigation the effect of neuroleptics on glutamate-mediated neurotransmission remains controversial. To study the effects of typical and atypical neuroleptics on selected parameters of glutamate-mediated neurotransmission, male Sprague-Dawley rats were randomly assigned to a 21-day oral treatment course with vehicle, haloperidol (HDL), or clozapine (CLZ). Coronal slices of rat brain were then incubated with tritiated ligands to measure NMDA, AMPA, and kainate receptor, and glutamate reuptake site density. Regions of interest included the frontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, and the nucleus accumbens. CLZ increased the density of AMPA receptors significantly in the frontal and anterior cingulate cortices compared with normal controls. In the dorsal and ventral striatum, and nucleus accumbens as a whole, CLZ-treated rats had a higher AMPA receptor density compared with both the HDL- and vehicle-treated controls. Additionally, within the nucleus accumbens, CLZ-treated rats had a higher density of AMPA receptors compared with the HDL group in the core, and at trend level in the shell. There was a group by region interaction for NMDA receptor density, primarily reflecting the tendency of HDL treated rats to have high receptor densities in the frontal and anterior cingulate cortices. Kainate receptors and glutamate reuptake site densities did not differ significantly across groups. These results suggest a critical role for glutamate in the mediation of atypical antipsychotic drug action in anatomically-specific regions, and further encourage the investigation of glutamate neurotransmitter systems in schizophrenia.

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“…It is unlikely that the facilitating effect of clozapine, halopericlol, and M100907 on NMDA-induced inward current results from a direct interaction with NMDA receptors because of the relatively iow affinity of these drugs for the 3 H-MK-801 binding sites (Lidsky et al 1993;Tarazi et al 1996) and became of the blockade of the potentiating effect by CNQX and by compounds that diminish the release of neurotransmitters (see below). It might be speculated that the biochemical mechanisms behind clozapine and haloperidol-induced potentiation of NMDA response are secondary to their binding to other receptor or effectcr systems.…”

Section: Discussionmentioning

confidence: 99%

M100907, A Selective 5-HT2A Receptor Antagonist and a Potential Antipsychotic Drug, Facilitates N-Methyl-D-Aspartate-Receptor Mediated Neurotransmission in the Rat Medial Prefrontal Cortical Neurons In Vitro

Arvanov

Wang

1998

Neuropsychopharmacology

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Anti-glutamatergic effects of clozapine

Cited by 51 publications

References 17 publications

Long-Term Effects of Olanzapine, Risperidone, and Quetiapine on Ionotropic Glutamate Receptor Types: Implications for Antipsychotic Drug Treatment

Long-Term Effects of Olanzapine, Risperidone, and Quetiapine on Ionotropic Glutamate Receptor Types: Implications for Antipsychotic Drug Treatment

Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats

M100907, A Selective 5-HT2A Receptor Antagonist and a Potential Antipsychotic Drug, Facilitates N-Methyl-D-Aspartate-Receptor Mediated Neurotransmission in the Rat Medial Prefrontal Cortical Neurons In Vitro

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