Does clozapine work by blocking spikes and sparing bursts?

Olson, Timothy P.

doi:10.1016/j.mehy.2005.01.035

Cited by 3 publications

(5 citation statements)

References 94 publications

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“…Yet, several objections have been raised against these propositions. For example, despite their full 5-HT 2A receptor occupy at clinically relevant doses, distinct antipsychotics do not trigger extrapyramidal side effects to the same extent (Kapur and Seeman 2000;Olson 2005), and the threshold D 2 receptor occupancy at which such side effects emerge does not depend on their 5-HT 2A antagonistic profile (Frankle et al 2004). In this respect, D 2 antagonists with highly unfavorable 5-HT 2A /D 2 receptor affinity ratio may also display excellent antipsychotic activity (Langlois et al 2010;Schmidt et al 2010).…”

Section: Atypical Antipsychoticsmentioning

confidence: 99%

“…Olson (2005) explored their ability to suppress single spikes (lasting 100 ms) and bursts (lasting 300 ms) while Kapur and Seeman (2001) explored the effect on a 5-min surge in dopamine concentration. Such surges have indeed been observed to last from seconds to several minutes (Kawagoe et al 1992;Koepp et al 1998;Salimpoor et al 2010).…”

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

“…For example, the integrals used by Olson (2005) only evoked the antagonist dissociation rate (implying dopamine association and dissociation and antagonist association to be instantaneous). In contrast, the present simulations are based on repeatedly, simultaneously implementing (typically 1,000 times per second) the underlying differential equations (1, 2, and 4 in Table 3) over very small time intervals (d(t)) as previously described (Vauquelin et al 2001).…”

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

“…At the present level of investigation, it is still not clear yet whether this is indeed the case. Finally, extra D 2 receptor stimulation during individual peaks in dopamine concentration becomes even more improbable since it should imply extremely fast dissociation of clozapine and quetiapine, i.e., with half-lives in the millisecond range such as already evoked by Olson (2005).…”

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

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Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Vauquelin

Bostoen

Vanderheyden

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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Drug-receptor interactions are traditionally quantified in terms of affinity and efficacy, but there is increasing awareness that the drug-on-receptor residence time also affects clinical performance. While most interest has hitherto been focused on slow-dissociating drugs, D(2) dopamine receptor antagonists show less extrapyramidal side effects but still have excellent antipsychotic activity when they dissociate swiftly. Fast dissociation of clozapine, the prototype of the "atypical antipsychotics", has been evidenced by distinct radioligand binding approaches both on cell membranes and intact cells. The surmountable nature of clozapine in functional assays with fast-emerging responses like calcium transients is confirmatory. Potential advantages and pitfalls of the hitherto used techniques are discussed, and recommendations are given to obtain more precise dissociation rates for such drugs. Surmountable antagonism is necessary to allow sufficient D(2) receptor stimulation by endogenous dopamine in the striatum. Simulations are presented to find out whether this can be achieved during sub-second bursts in dopamine concentration or rather during much slower, activity-related increases thereof. While the antagonist's dissociation rate is important to distinguish between both mechanisms, this becomes much less so when contemplating time intervals between successive drug intakes, i.e., when pharmacokinetic considerations prevail. Attention is also drawn to the divergent residence times of hydrophobic antagonists like haloperidol when comparing radioligand binding data on cell membranes with those on intact cells and clinical data.

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Section: Atypical Antipsychoticsmentioning

confidence: 99%

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

Section: Impact Of the Antipsychotic Dissociation Rate On D 2 Receptomentioning

confidence: 99%

See 2 more Smart Citations

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Vauquelin

Bostoen

Vanderheyden

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Equally interesting, the loose-binding hypothesis postulates that CLZ acts by transiently blocking DRD2 [29]. Studies based on mathematical modeling of receptor occupancy also suggest that CLZ can block single DRD2-induced neuronal spikes, but it does not block spikes that mediate locomotion, cognition, and affect [30]. Moreover, in vitro studies on DRD2 overexpression indicate that CLZ binds to DRD2 with a high level of affinity [31].…”

Section: Changes In Gene Expression After Clz Administrationmentioning

confidence: 99%

Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study

Korlatowicz

Kuśmider

Szlachta

et al. 2021

IJMS

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Background: Cognitive disorders associated with schizophrenia are closely linked to prefrontal cortex (PFC) dysfunction. Administration of the non-competitive NMDA receptor antagonist ketamine (KET) induces cognitive impairment in animals, producing effects similar to those observed in schizophrenic patients. In a previous study, we showed that KET (20 mg/kg) induces cognitive deficits in mice and that administration of clozapine (CLZ) reverses this effect. To identify biochemical mechanisms related to CLZ actions in the context of KET-induced impairment, we performed a biochemical analysis using the same experimental paradigm—acute and sub-chronic administration of these drugs (0.3 and 1 mg/kg). Methods: Since the effect of CLZ mainly depends on G-protein-related receptors, we used the Signaling PathwayFinder Kit to identify 84 genes involved in GPCR-related signal transduction and then verified the genes that were statistically significantly different on a larger group of mice using RT-PCR and Western blot analyses after the administration of acute and sub-chronic drugs. Results: Of the 84 genes involved in GPCR-related signal transduction, the expression of six, βarrestin1, βarrestin2, galanin receptor 2 (GalR2), dopamine receptor 2 (DRD2), metabotropic glutamate receptor 1 (mGluR1), and metabotropic glutamate receptor 5 (mGluR5), was significantly altered. Since these genes affect the levels of other signaling proteins, e.g., extracellular signal-regulated kinase 1/2 (ERK1/2), G protein-coupled receptor kinase 2 (Grk2), and G protein-gated inwardly rectifying potassium 3 (Girk3), we determined their levels in PFC using Western blot. Most of the observed changes occurred after acute treatment with 0.3 mg/kg CLZ. We showed that acute treatment with CLZ at a lower dose significantly increased βarrestin1 and ERK1/2. KET treatment induced the upregulation of βarrestin1. Joint administration of these drugs had no effect on the βarrestin1 level. Conclusion: The screening kit we used to study the expression of GPCR-related signal transduction allowed us to select several important genes affected by CLZ. However, the obtained data do not explain the mechanism of action of CLZ that is responsible for reversing KET-induced cognitive impairment.

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The role of D1–D2 receptor hetero-dimerization in the mechanism of action of clozapine

Faron-Górecka

Górecki

Kuśmider

et al. 2008

European Neuropsychopharmacology

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Does clozapine work by blocking spikes and sparing bursts?

Cited by 3 publications

References 94 publications

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study

The role of D1–D2 receptor hetero-dimerization in the mechanism of action of clozapine

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