Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice

Hideshima, Kelsey S.; Hojati, Ashkhan; Saunders, Justin M.; On, Doan M.; Revenga, Mario de la Fuente; Shin, Jong M.; Sánchez-González, Ana; Dunn, Cassandra M; Pais, Alexander B; Pais, A. Christian; Miles, Michael F.; Wolstenholme, Jennifer T.; González-Maeso, Javier

doi:10.1007/s00213-018-5015-4

Cited by 16 publications

(14 citation statements)

References 65 publications

(103 reference statements)

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“…Locomotor activity was monitored as previously described ( 66 ), with minor changes. Briefly, animals were injected with DOI (2 mg/kg, i.p.)…”

Section: Methodsmentioning

confidence: 99%

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Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Revenga

Zhu

Guevara

et al. 2021

Preprint

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Clinical evidence suggests a potential therapeutic effect of classic psychedelics for the treatment of depression. The most outstanding and distinct characteristic is the rapid and sustained antidepressant action with one single exposure to the drug. However, the biological substrates and key mediators of psychedelics' enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produced fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI led to changes in chromatin organization particularly at enhancer regions of genes involved in synaptic assembly that stretched for days after the psychedelic exposure. DOI-induced alterations in neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression and attention deficit hyperactivity disorder. Together, these data support the notion that epigenetic-driven changes in synaptic plasticity operate as the mechanistic substrate of psychedelic's long-lasting antidepressant action but also warn on the limitations in individuals with underlying risk for psychosis.

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“…Locomotor activity was monitored as previously described ( 66 ), with minor changes. Briefly, animals were injected with DOI (2 mg/kg, i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…Breeders were backcrossed from 129S6/SvEv onto C57BL/6 for several generations (F5 was used for behavioral paradigms).Locomotor activity. Locomotor activity was monitored as previously described(66), with minor changes. Briefly, animals were injected with DOI (2 mg/kg, i.p.)…”

mentioning

confidence: 99%

Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Revenga

Zhu

Guevara

et al. 2021

Preprint

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“…While the mechanism controlling the dimerization process is still unclear and research have afforded diverse explanations for their assemblies, physical interactions between class A and class C GPRCs have been reported, evincing the formation of heterodimers. These heterodimers include mGluR/serotonin 5-HT 2A receptor (5-HT 2A R), mGlu5/adenosine A 2A R (A2AR), Glu5/dopamine D1 receptor (D1R), and mGlu5/mu-opioid receptor (MOR) [26,[67][68][69][70][71][72]. Among these heterodimers, mGlu2/5-HT 2A R is the most widely investigated and association to the pathophysiology of psychosis in schizophrenia and Parkinson's disease, as well as dyskinesia in the latter rendered this heterodimer an attractive target for the treatment of these diseases [68][69][70]73].…”

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 99%

“…These heterodimers include mGluR/serotonin 5-HT 2A receptor (5-HT 2A R), mGlu5/adenosine A 2A R (A2AR), Glu5/dopamine D1 receptor (D1R), and mGlu5/mu-opioid receptor (MOR) [26,[67][68][69][70][71][72]. Among these heterodimers, mGlu2/5-HT 2A R is the most widely investigated and association to the pathophysiology of psychosis in schizophrenia and Parkinson's disease, as well as dyskinesia in the latter rendered this heterodimer an attractive target for the treatment of these diseases [68][69][70]73].…”

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 99%

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Lazim¹,

Suh²,

Lee³

et al. 2021

IJMS

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G protein-coupled receptor (GPCR) oligomerization, while contentious, continues to attract the attention of researchers. Numerous experimental investigations have validated the presence of GPCR dimers, and the relevance of dimerization in the effectuation of physiological functions intensifies the attractiveness of this concept as a potential therapeutic target. GPCRs, as a single entity, have been the main source of scrutiny for drug design objectives for multiple diseases such as cancer, inflammation, cardiac, and respiratory diseases. The existence of dimers broadens the research scope of GPCR functions, revealing new signaling pathways that can be targeted for disease pathogenesis that have not previously been reported when GPCRs were only viewed in their monomeric form. This review will highlight several aspects of GPCR dimerization, which include a summary of the structural elucidation of the allosteric modulation of class C GPCR activation offered through recent solutions to the three-dimensional, full-length structures of metabotropic glutamate receptor and γ-aminobutyric acid B receptor as well as the role of dimerization in the modification of GPCR function and allostery. With the growing influence of computational methods in the study of GPCRs, we will also be reviewing recent computational tools that have been utilized to map protein–protein interactions (PPI).

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“…According to numerous reports, G protein-coupled receptors may form heterodimers or oligomers with the same or other types of receptors, indicating strong multiple interactions between two or more receptors [ 241 , 242 , 243 , 244 , 245 , 246 , 247 ]. mGlu 2 -5-HT 2A heterodimerization is one of the most important pathways implicated in schizophrenia [ 248 , 249 , 250 ]. Other forms of heterocomplexes in relation to schizophrenia have also been described, such as the mGlu 5 /D 2 /A 2A oligomer [ 251 , 252 ].…”

Section: Strategies Based On Bidirectional Inhibition Of Glutamatementioning

confidence: 99%

Regulation of Glutamatergic Activity via Bidirectional Activation of Two Select Receptors as a Novel Approach in Antipsychotic Drug Discovery

Cieślik

Wierońska

2020

IJMS

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Schizophrenia is a mental disorder that affects approximately 1–2% of the population and develops in early adulthood. The disease is characterized by positive, negative, and cognitive symptoms. A large percentage of patients with schizophrenia have a treatment-resistant disease, and the risk of developing adverse effects is high. Many researchers have attempted to introduce new antipsychotic drugs to the clinic, but most of these treatments failed, and the diversity of schizophrenic symptoms is one of the causes of disappointing results. The present review summarizes the results of our latest papers, showing that the simultaneous activation of two receptors with sub-effective doses of their ligands induces similar effects as the highest dose of each compound alone. The treatments were focused on inhibiting the increased glutamate release responsible for schizophrenia arousal, without interacting with dopamine (D2) receptors. Ligands activating metabotropic receptors for glutamate, GABAB or muscarinic receptors were used, and the compounds were administered in several different combinations. Some combinations reversed all schizophrenia-related deficits in animal models, but others were active only in select models of schizophrenia symptoms (i.e., cognitive or negative symptoms).

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Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice

Abstract: These findings further support the existence of a functionally relevant crosstalk between 5-HT and mGlu2 receptors in different preclinical models of antipsychotic activity.

Cited by 16 publications

References 65 publications

Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Regulation of Glutamatergic Activity via Bidirectional Activation of Two Select Receptors as a Novel Approach in Antipsychotic Drug Discovery

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