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Article ; Online: Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia.

Dogra, Shalini / Conn, P Jeffrey

2022 Volume 101, Issue 5, Page(s) 275–285

Abstract: Accumulating evidence of glutamatergic abnormalities in the brains of schizophrenia patients has led to efforts to target various components of glutamatergic signaling as potential new approaches for schizophrenia. Exciting research suggests that ... ...

Abstract	Accumulating evidence of glutamatergic abnormalities in the brains of schizophrenia patients has led to efforts to target various components of glutamatergic signaling as potential new approaches for schizophrenia. Exciting research suggests that metabotropic glutamate (mGlu) receptors could provide a fundamentally new approach for better symptomatic relief in patients with schizophrenia. In preclinical studies, the mGlu
MeSH term(s)	Allosteric Regulation ; Animals ; Antipsychotic Agents/pharmacology ; Antipsychotic Agents/therapeutic use ; Glutamic Acid ; Humans ; Receptor, Metabotropic Glutamate 5/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Schizophrenia/drug therapy
Chemical Substances	Antipsychotic Agents ; Receptor, Metabotropic Glutamate 5 ; Receptors, N-Methyl-D-Aspartate ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2022-03-03
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.121.000460
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Article ; Online: Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.

Luessen, Deborah J / Conn, P Jeffrey

Pharmacological reviews

2022 Volume 74, Issue 3, Page(s) 630–661

Abstract: Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous ...

Abstract	Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. SIGNIFICANCE STATEMENT: Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.
MeSH term(s)	Allosteric Regulation/physiology ; Binding Sites ; Brain Diseases ; Glutamic Acid ; Humans ; Receptors, Metabotropic Glutamate/chemistry ; Receptors, Metabotropic Glutamate/metabolism
Chemical Substances	Receptors, Metabotropic Glutamate ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pharmrev.121.000540
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Article ; Online: Targeting metabotropic glutamate receptors for the treatment of depression and other stress-related disorders.

Dogra, Shalini / Conn, P Jeffrey

Neuropharmacology

2021 Volume 196, Page(s) 108687

Abstract: The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, ... ...

Abstract	The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, compounds acting at metabotropic glutamate (mGlu) receptors are among the most promising agents under studies for depressive disorders. Further, the receptor diversity, distinct distribution in the CNS, and ability to modulate the glutamatergic neurotransmission in the brain areas implicated in mood disorders make them an exciting target for stress-related disorders. In preclinical models, antidepressant and anxiolytic effects of mGlu
MeSH term(s)	Allosteric Regulation ; Animals ; Anxiety Disorders/drug therapy ; Brain/metabolism ; Depressive Disorder, Major/drug therapy ; Depressive Disorder, Treatment-Resistant/drug therapy ; Excitatory Amino Acid Antagonists/therapeutic use ; Humans ; Ketamine/therapeutic use ; Molecular Targeted Therapy ; Receptor, Metabotropic Glutamate 5/antagonists & inhibitors ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Stress, Psychological/drug therapy
Chemical Substances	Excitatory Amino Acid Antagonists ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate ; metabotropic glutamate receptor 2 ; metabotropic glutamate receptor 3 ; metabotropic glutamate receptor type 1 ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2021-06-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2021.108687
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Article ; Online: Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Nunes, Eric J / Addy, Nii A / Conn, P Jeffrey / Foster, Daniel J

Annual review of pharmacology and toxicology

2023 Volume 64, Page(s) 277–289

Abstract: Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal ... ...

Abstract	Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.
MeSH term(s)	Humans ; Dopamine ; Receptors, Muscarinic/metabolism ; Corpus Striatum/metabolism ; Signal Transduction
Chemical Substances	Dopamine (VTD58H1Z2X) ; Receptors, Muscarinic
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	196587-6
ISSN	1545-4304 ; 0362-1642
ISSN (online)	1545-4304
ISSN	0362-1642
DOI	10.1146/annurev-pharmtox-051921-023858
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Article ; Online: Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders.

Dogra, Shalini / Putnam, Jason / Conn, P Jeffrey

Pharmacology, biochemistry, and behavior

2022 Volume 221, Page(s) 173493

Abstract: Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 ( ... ...

Abstract	Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu
MeSH term(s)	Humans ; Receptors, Metabotropic Glutamate ; Nervous System Diseases/drug therapy ; Central Nervous System ; Glutamic Acid
Chemical Substances	metabotropic glutamate receptor 3 ; Receptors, Metabotropic Glutamate ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2022-11-17
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	191042-5
ISSN	1873-5177 ; 0091-3057
ISSN (online)	1873-5177
ISSN	0091-3057
DOI	10.1016/j.pbb.2022.173493
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Article ; Online: Leveraging bias to your advantage.

Moran, Sean P / Conn, P Jeffrey

Nature chemical biology

2020 Volume 16, Issue 3, Page(s) 226–227

MeSH term(s)	Animals ; Cholinergic Agents ; Mice ; Receptor, Muscarinic M1
Chemical Substances	Cholinergic Agents ; Receptor, Muscarinic M1
Language	English
Publishing date	2020-02-17
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-020-0468-2
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Zs.A 6251: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Roles of the M

Moehle, Mark S / Conn, P Jeffrey

Movement disorders : official journal of the Movement Disorder Society

2019 Volume 34, Issue 8, Page(s) 1089–1099

Abstract: Acetylcholine (ACh) released from cholinergic interneurons acting through nicotinic and muscarinic acetylcholine receptors (mAChRs) in the striatum have been thought to be central for the potent cholinergic regulation of basal ganglia activity and motor ... ...

Abstract	Acetylcholine (ACh) released from cholinergic interneurons acting through nicotinic and muscarinic acetylcholine receptors (mAChRs) in the striatum have been thought to be central for the potent cholinergic regulation of basal ganglia activity and motor behaviors. ACh activation of mAChRs has multiple actions to oppose dopamine (DA) release, signaling, and related motor behaviors and has led to the idea that a delicate balance of DA and mAChR signaling in the striatum is critical for maintaining normal motor function. Consistent with this, mAChR antagonists have efficacy in reducing motor symptoms in diseases where DA release or signaling is diminished, such as in Parkinson's disease and dystonia, but are limited in their utility because of severe adverse effects. Recent breakthroughs in understanding both the anatomical sites of action of ACh and the mAChR subtypes involved in regulating basal ganglia function reveal that the M
MeSH term(s)	Acetylcholine/metabolism ; Basal Ganglia/metabolism ; Cholinergic Neurons/metabolism ; Dopamine/metabolism ; Dystonia/drug therapy ; Dystonia/metabolism ; Glutamic Acid/metabolism ; Humans ; Interneurons/metabolism ; Molecular Targeted Therapy ; Movement Disorders/drug therapy ; Movement Disorders/metabolism ; Muscarinic Antagonists/therapeutic use ; Neostriatum/metabolism ; Parkinson Disease/drug therapy ; Parkinson Disease/metabolism ; Receptor, Muscarinic M4/antagonists & inhibitors ; Receptor, Muscarinic M4/metabolism ; Receptors, Dopamine/metabolism ; Synaptic Transmission
Chemical Substances	Muscarinic Antagonists ; Receptor, Muscarinic M4 ; Receptors, Dopamine ; Glutamic Acid (3KX376GY7L) ; Acetylcholine (N9YNS0M02X) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2019-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.27740
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Zs.A 2555: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors.

Stansley, Branden J / Conn, P Jeffrey

Trends in pharmacological sciences

2019 Volume 40, Issue 4, Page(s) 240–252

Abstract: The metabotropic glutamate (mGlu) receptors are a family of G-protein-coupled receptors (GPCRs) that regulate cell physiology throughout the nervous system. The potential of mGlu receptors as therapeutic targets has been bolstered by current research ... ...

Abstract	The metabotropic glutamate (mGlu) receptors are a family of G-protein-coupled receptors (GPCRs) that regulate cell physiology throughout the nervous system. The potential of mGlu receptors as therapeutic targets has been bolstered by current research that has provided insight into the diverse modes of mGlu activation and signaling. In particular, the allosteric modulation of mGlu receptors represents a major area of focus in studies of basic pharmacology as well as drug development, largely due to the high subtype specificity achievable by targeting allosteric sites on mGlu receptors. These provide sophisticated regulation of neuronal excitability and synaptic transmission to influence behavioral output. Here, we review how these allosteric mechanisms have been leveraged preclinically to demonstrate the therapeutic potential of allosteric modulators for neurological and neuropsychiatric disorders, such as autism, cognitive impairment, Parkinson's disease (PD), stress, and schizophrenia.
MeSH term(s)	Allosteric Regulation ; Allosteric Site ; Animals ; Drug Development ; Humans ; Mental Disorders/drug therapy ; Mental Disorders/physiopathology ; Receptors, Metabotropic Glutamate/drug effects ; Receptors, Metabotropic Glutamate/metabolism ; Synaptic Transmission
Chemical Substances	Receptors, Metabotropic Glutamate
Language	English
Publishing date	2019-02-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2019.02.006
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Article ; Online: Targeting muscarinic receptors to treat schizophrenia.

Foster, Daniel J / Bryant, Zoey K / Conn, P Jeffrey

Behavioural brain research

2021 Volume 405, Page(s) 113201

Abstract: Schizophrenia is a severe neuropsychiatric disorder characterized by a diverse range of symptoms that can have profound impacts on the lives of patients. Currently available antipsychotics target dopamine receptors, and while they are useful for ... ...

Abstract	Schizophrenia is a severe neuropsychiatric disorder characterized by a diverse range of symptoms that can have profound impacts on the lives of patients. Currently available antipsychotics target dopamine receptors, and while they are useful for ameliorating the positive symptoms of the disorder, this approach often does not significantly improve negative and cognitive symptoms. Excitingly, preclinical and clinical research suggests that targeting specific muscarinic acetylcholine receptor subtypes could provide more comprehensive symptomatic relief with the potential to ameliorate numerous symptom domains. Mechanistic studies reveal that M1, M4, and M5 receptor subtypes can modulate the specific brain circuits and physiology that are disrupted in schizophrenia and are thought to underlie positive, negative, and cognitive symptoms. Novel therapeutic strategies for targeting these receptors are now advancing in clinical and preclinical development and expand upon the promise of these new treatment strategies to potentially provide more comprehensive relief than currently available antipsychotics.
MeSH term(s)	Animals ; Antipsychotic Agents/pharmacology ; Clozapine/pharmacology ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/etiology ; Humans ; Muscarinic Agonists/pharmacology ; Pyridines/pharmacology ; Receptors, Muscarinic/drug effects ; Schizophrenia/complications ; Schizophrenia/drug therapy ; Schizophrenia/physiopathology ; Thiadiazoles/pharmacology
Chemical Substances	Antipsychotic Agents ; Muscarinic Agonists ; Pyridines ; Receptors, Muscarinic ; Thiadiazoles ; xanomeline (9ORI6L73CJ) ; Clozapine (J60AR2IKIC)
Language	English
Publishing date	2021-02-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	449927-x
ISSN	1872-7549 ; 0166-4328
ISSN (online)	1872-7549
ISSN	0166-4328
DOI	10.1016/j.bbr.2021.113201
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Article ; Online: Increased Synaptic Strength and mGlu

Joffe, Max E / Winder, Danny G / Conn, P Jeffrey

Alcoholism, clinical and experimental research

2021 Volume 45, Issue 3, Page(s) 518–529

Abstract: Background: The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been ... ...

Abstract	Background: The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus). Methods: In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1 day after 4 to 5 weeks of intermittent access (IA) EtOH exposure. Results: Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu Conclusions: Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu
MeSH term(s)	Animals ; Ethanol/administration & dosage ; Excitatory Postsynaptic Potentials/drug effects ; Excitatory Postsynaptic Potentials/physiology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuronal Plasticity/drug effects ; Neuronal Plasticity/physiology ; Prefrontal Cortex/cytology ; Prefrontal Cortex/drug effects ; Prefrontal Cortex/physiology ; Pyramidal Cells/drug effects ; Pyramidal Cells/physiology ; Receptors, Metabotropic Glutamate/physiology ; Synapses/drug effects ; Synapses/physiology
Chemical Substances	Receptors, Metabotropic Glutamate ; metabotropic glutamate receptor 2 ; metabotropic glutamate receptor 3 ; Ethanol (3K9958V90M)
Language	English
Publishing date	2021-02-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	428999-7
ISSN	1530-0277 ; 0145-6008
ISSN (online)	1530-0277
ISSN	0145-6008
DOI	10.1111/acer.14546
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