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

Faron-Górecka, Agata; Górecki, Andrzej; Kuśmider, Maciej; Wasylewski, Zygmunt; Dziedzicka-Wasylewska, Marta

doi:10.1016/j.euroneuro.2008.05.001

Cited by 39 publications

(30 citation statements)

References 49 publications

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“…The receptors are also often over-expressed in such cell lines. This may engender phenomena like constitutive receptor activity (drawing excessive attention on inverse agonism), the emergence of earlier conceptualized D 1 -D 2 receptor heterodimers Faron-Górecka et al 2008) and for excessively high agonist potencies (even in case of adenylate cyclase activity inhibition) and efficacies (i.e., maximal levels of response) of partial agonists (Black and Leff 1983;Brink et al 2000).…”

Section: In Vitro Studies: Prospects and Limitationsmentioning

confidence: 98%

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: In Vitro Studies: Prospects and Limitationsmentioning

confidence: 98%

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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“…Such findings may be related to an imbalance of dopamine receptors. Our previous study using an in vitro model demonstrated that a lower dose of CLZ (acting on dopamine receptors in high affinity states, which are the active state of receptors) uncoupled D1-D2 heterodimers, whereas a higher dose of CLZ increased D1-D2 heterodimerization; these scenarios produced different effects on the intracellular signalling pathway involving phospholipase C-mediated calcium mobilization (Faron-Górecka et al 2008). …”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies using an in vitro model, we demonstrated the effects of CLZ on D1-D2 receptor heterodimers. The effect was strongly CLZ concentration dependent; lower concentrations, which result in binding to high affinity sites, decreased the physical interaction between these two dopamine sub-receptors, whereas higher concentrations of CLZ increased physical interactions (Faron-Górecka et al 2008). Concentration-dependent actions of CLZ were also observed in studies of 5HT1A-D2 heterodimers (Lukasiewicz et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Effect of clozapine on ketamine-induced deficits in attentional set shift task in mice

et al. 2017

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RationaleClozapine (CLZ) is an effective treatment for schizophrenia, producing improvements in both negative symptoms and cognitive impairments. Cognitive impairments can be modelled in animals by ketamine (KET) and assessed using the attentional set-shift task (ASST).ObjectiveOur first aim was to determine whether CLZ improves cognitive function and reverses KET-induced cognitive impairments using the ASST. Our second aim was to assess dose dependency of these effects.ResultsOur findings demonstrate that acute as well as sub-chronic administration of KET cause cognitive deficits observed as increase in number of trails and errors to reach the criterion in the EDS phase. CLZ 0.3 mg/kg reversed the effects of both acute and sub-chronic KET, with no effects on locomotor activity. However, clozapine’s effect after sub-chronic administration of dose 0.3 mg/kg was not as explicit as in the case of acute treatment. Moreover, administration of 1 mg/kg CLZ to KET-treated mice induced or enhanced deficits in the extra-dimensional shift phase compared to 1 mg/kg CLZ administration to mice not receiving KET. Locomotor activity test showed sedation effects of CLZ 1 mg/kg after acute treatment; therefore, effect of CLZ 1 mg/kg on KET-induced cognitive deficits was not evaluated in the attentional set-shift task (ASST) test.ConclusionsThe present findings support dose-dependent effects of CLZ to reverse KET-induced cognitive deficits. The observed dose dependency may be mediated by activation of different receptors, including monomers and/or heterodimers.

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“…288,289 Moreover, FRET assays showed that clozapine appears to modulate the formation of D1R–D2R heteromers in that high concentrations of the drug increase the FRET signal between D1R and D2R while low concentrations attenuate this signal. 288,289 Further support for the involvement D1R–D2R heteromers in schizophrenia came from studies showing that acute treatment with a heteromer-selective agonist increased the striatal expression of brain-derived neurotrophic factor, a molecule that has been linked to schizophrenia (for review, see Ref. 290).…”

Section: Heteromers In Diseasementioning

confidence: 99%

Disease-Specific Heteromerization of G-Protein-Coupled Receptors That Target Drugs of Abuse

Gomes

Fujita

Chandrakala

et al. 2013

Progress in Molecular Biology and Translational Science

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Drugs of abuse such as morphine or marijuana exert their effects through the activation of G-protein-coupled receptors (GPCRs), the opioid and cannabinoid receptors, respectively. Moreover, interactions between either of these receptors have been shown to be involved in the rewarding effects of drugs of abuse. Recent advances in the field, using a variety of approaches, have demonstrated that many GPCRs, including opioid, cannabinoid, and dopamine receptors, can form associations between different receptor subtypes or with other GPCRs to form heteromeric complexes. The formation of these complexes, in turn, leads to the modulation of the properties of individual protomers. The development of tools that can selectively disrupt GPCR heteromers as well as monoclonal antibodies that can selectively block signaling by specific heteromer pairs has indicated that heteromers involving opioid, cannabinoid, or dopamine receptors may play a role in various disease states. In this review, we describe evidence for opioid, cannabinoid, and dopamine receptor heteromerization and the potential role of GPCR heteromers in pathophysiological conditions.

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

Cited by 39 publications

References 49 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

Effect of clozapine on ketamine-induced deficits in attentional set shift task in mice

Disease-Specific Heteromerization of G-Protein-Coupled Receptors That Target Drugs of Abuse

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