Pharmacology and Therapeutic Potential of the 5-HT<sub>7</sub> Receptor

Blattner, Kevin M.; Canney, Daniel J.; Pippin, Douglas; Blass, Benjamin E.

doi:10.1021/acschemneuro.8b00283

Cited by 39 publications

(34 citation statements)

References 331 publications

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“…The 5-HT7R, the last discovered member of the 5-HTR family [33,34], has always been the subject of intense investigation, due to its high expression in functionally relevant regions of the brain [35,36]. Accordingly, several recent data have elucidated its role in a wide range of physiological functions in the mammalian CNS and also in peripheral organs [37]. Interestingly, emerging findings indicate that 5-HT7R is involved in brain plasticity, being one of the players contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling higher cognitive functions (see Sections 2.2 and 2.3).…”

Section: The 5-ht7rmentioning

confidence: 99%

“…In the mammalian CNS, the 5-HT7R is mainly expressed in the spinal cord, thalamus, hypothalamus, hippocampus, prefrontal cortex, striatal complex, amygdala and in the Purkinje neurons of the cerebellum [40,41]. This wide distribution reflects the numerous functions in which the receptor is involved, such as circadian rhythms, sleep-wake cycle, thermoregulation, learning and memory processing, and nociception [37].…”

Section: The 5-ht7rmentioning

confidence: 99%

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Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Crispino

Volpicelli

Perrone-Capano

2020

IJMS

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Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows the rescue of long-term potentiation (LTP) and long-term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, modulates the function of immune cells, and is likely to play a role in the gut-brain axis. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gastrointestinal (GI) tract and immune system.

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Section: The 5-ht7rmentioning

confidence: 99%

Section: The 5-ht7rmentioning

confidence: 99%

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Crispino

Volpicelli

Perrone-Capano

2020

IJMS

View full text Add to dashboard Cite

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“…In the mammalian CNS, the 5-HT7R is mainly expressed in spinal cord, thalamus, hypothalamus, hippocampus, prefrontal cortex, striatal complex, amygdala and in the Purkinje neurons of the cerebellum [35,36]. This wide distribution reflects the numerous functions in which the receptor is involved, such as circadian rhythms, sleep-wake cycle, thermoregulation, learning and memory processing, and nociception [37]. It is noteworthy that, in mammals, this receptor exhibits a number of functional splice variants due to the presence of introns in the 5-HT7R gene [38].…”

Section: The 5-ht7rmentioning

confidence: 99%

“…Numerous brain disorders, such as ASD, cognitive and mood dysfunctions, schizophrenia, depression, anxiety, impulsivity, epilepsy, migraine and neuropathic pain show altered 5-HT7Rmediated signaling [37,79]. The potential involvement of 5-HT7R in most of these diseases was discovered studying the effects of a broad range of antidepressant and antipsychotic drugs that interact with the receptor, displaying high affinity [40].…”

Section: The 5-ht7r and Neurological Diseasesmentioning

confidence: 99%

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Crispino

Volpicelli

Perrone-Capano

2019

Preprint

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Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology considerably advanced in the last few years. A wealth of data show that the 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows to rescue long term potentiation (LTP) and long term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, possibly playing a role in the gut-brain axis, and modulates the function of immune cells. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gut and immune system.

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“…Preliminary CNS IRL752 exposure data concur with this prediction. Although antagonism of 5-HT7 receptors has been demonstrated to contribute to enhanced cortical DA efflux, the neuronal localization of any such action remains to be determined (see Wesołowska and Kowalska, 2008;Blattner et al, 2019). Selective blockade of a2C-adrenoreceptors relative to (mainly postsynaptic; Erdozain et al, 2019) a2Aadrenoceptors also seems to promote DA in the PFC (see Uys et al, 2017a, and references cited within), whereas a2Aadrenoceptor antagonism may be important for boosting ACh output (Zaborszky et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

Stephan

Waters

Tedroff

et al. 2020

J Pharmacol Exp Ther

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Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)-and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognitionrelated immediate early genes (IEGs), however, increased by 1.5fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmissionpromoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and a2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

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Pharmacology and Therapeutic Potential of the 5-HT₇ Receptor

Cited by 39 publications

References 331 publications

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

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Pharmacology and Therapeutic Potential of the 5-HT7 Receptor

Cited by 39 publications

References 331 publications

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

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Pharmacology and Therapeutic Potential of the 5-HT₇ Receptor