Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats

Ahnaou, A.; Langlois, Xavier; Steckler, Thomas; Bartolomé-Nebreda, José Manuel; Drinkenburg, Wilhelmus

doi:10.1007/s00213-014-3746-4

Cited by 28 publications

(35 citation statements)

References 89 publications

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“…These studies collectively showed a significant increase of REM after drug administration. Further, both Harvey et al (2013) and Ahnaou et al (2014) reported an increase of time spent in wakefulness and increased sleep consolidation. In contrast to our results, however, Ahnaou et al (2014) reported a rebound in REM during the dark period after administration of MTEP; nonetheless, Ahnaou et al (2014) concluded that mGlu5 inhibition has overall sleep consolidating effects, which they speculate might indirectly have beneficial effects on cognitive and memory performance.…”

Section: Discussionmentioning

confidence: 92%

“…The wakepromoting features of basimglurant, which occur in a consolidated manner, hold potential benefits in addressing the daytime sleepiness, lethargy, and apathy characteristic of MDD. The effects of mGlu5 inhibition on the EEG profile in rats were studied previously with a range of compounds, including MPEP, MTEP, GRN-529, and mavoglurant (Cavas et al, 2013;Harvey et al, 2013;Ahnaou et al, 2014). These studies collectively showed a significant increase of REM after drug administration.…”

Section: Discussionmentioning

confidence: 99%

“…The literature and our own work suggest that mGlu2/3 inhibitors have procognitive properties in a range of preclinical models of short-term and long-term memory, executive function, and impulse control (Higgins et al, 2004;Spinelli et al, 2005;Marek, 2010;Goeldner et al, 2013), which makes them interesting candidates to address cognitive deficits in MDD (Goeldner et al, 2013). For mGlu5, the situation is different because studies conducted in wild-type animals suggest that mGlu5 NAMs in general have no procognitive properties (Petersen et al, 2002;Ballard et al, 2005;Ahnaou et S.E.M., with n = 8 rats per group. *P , 0.05 versus vehicle based on a one-way (B and F) and two-way analysis of variance (C-E and G-H) followed by a two-tailed post hoc paired t test.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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“…[6]), and for investigating neurocognition (e.g. [7,8]). Furthermore, EEG topography helped to reintroduce EEG by means of theta cordance as a diagnostic marker for depression [9] and as a personalized treatment-response biomarker for antidepressants [10,11].…”

Section: Introductionmentioning

confidence: 99%

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

Drinkenburg

Ruigt²,

Ahnaou

2015

Neuropsychobiology

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The contemporary value of animal pharmaco-electroencephalography (p-EEG)-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. While p-EEG in humans and animals has been shown to be closely related in terms of underlying neuronal substrates, both translational and back-translational approaches are being used to address extrapolation issues and optimize the translational validity of preclinical animal p-EEG paradigms and data. Present applications build further on animal p-EEG and pharmaco-sleep EEG findings, but also on stimulation protocols, more specifically pharmaco-event-related potentials. Pharmaceutical research into novel treatments for neurological and psychiatric diseases has employed an increasing number of pharmacological as well as transgenic models to assess the potential therapeutic involvement of different neurochemical systems and novel drug targets as well as underlying neuronal connectivity and synaptic function. Consequently, p-EEG studies, now also readily applied in modeled animals, continue to have an important role in drug discovery and development, with progressively more emphasis on its potential as a central readout for target engagement and as a (translational) functional marker of neuronal circuit processes underlying normal and pathological brain functioning. In a similar vein as was done for human p-EEG studies, the contribution of animal p-EEG studies can further benefit by adherence to guidelines for methodological standardization, which are presently under construction by the International Pharmaco-EEG Society (IPEG).

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“…The central activity of ligands acting at 5HT7, mGluR2, mGluR5, mGluR7 and MCH1 has been characterised in rodents: inhibition of REM sleep occurrence was observed with 5HT7 antagonists [79,80,81], mGuR2 agonist and positive allosteric modulators (PAMs) [82,83], and with mGluR7 PAMs [84]. While mGluR2 antagonists and negative allosteric modulators (NAMs) and mGluR5 PAMs exhibit arousal-promoting properties [85,86,87], mGluR5 NAMs consolidated deep sleep time and cortical delta activity in preclinical as well as clinical studies [85,88,89]. Lastly, MCH1 antagonists decreased deep sleep without homeostatic recovery sleep [48].…”

Section: P-sleep As a Tool For Drug Profilingmentioning

confidence: 99%

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications

Drinkenburg

Ahnaou²,

Ruigt³

2015

Neuropsychobiology

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Current research on the effects of pharmacological agents on human neurophysiology finds its roots in animal research, which is also reflected in contemporary animal pharmaco-electroencephalography (p-EEG) applications. The contributions, present value and translational appreciation of animal p-EEG-based applications are strongly interlinked with progress in recording and neuroscience analysis methodology. After the pioneering years in the late 19th and early 20th century, animal p-EEG research flourished in the pharmaceutical industry in the early 1980s. However, around the turn of the millennium the emergence of structurally and functionally revealing imaging techniques and the increasing application of molecular biology caused a temporary reduction in the use of EEG as a window into the brain for the prediction of drug efficacy. Today, animal p-EEG is applied again for its biomarker potential - extensive databases of p-EEG and polysomnography studies in rats and mice hold EEG signatures of a broad collection of psychoactive reference and test compounds. A multitude of functional EEG measures has been investigated, ranging from simple spectral power and sleep-wake parameters to advanced neuronal connectivity and plasticity parameters. Compared to clinical p-EEG studies, where the level of vigilance can be well controlled, changes in sleep-waking behaviour are generally a prominent confounding variable in animal p-EEG studies and need to be dealt with. Contributions of rodent pharmaco-sleep EEG research are outlined to illustrate the value and limitations of such preclinical p-EEG data for pharmacodynamic and chronopharmacological drug profiling. Contemporary applications of p-EEG and pharmaco-sleep EEG recordings in animals provide a common and relatively inexpensive window into the functional brain early in the preclinical and clinical development of psychoactive drugs in comparison to other brain imaging techniques. They provide information on the impact of drugs on arousal and sleep architecture, assessing their neuropharmacological characteristics in vivo, including central exposure and information on kinetics. In view of the clear disadvantages as well as advantages of animal p-EEG as compared to clinical p-EEG, general statements about the usefulness of EEG as a biomarker to demonstrate the translatability of p-EEG effects should be made with caution, however, because they depend on the particular EEG or sleep parameter that is being studied. The contribution of animal p-EEG studies to the translational characterisation of centrally active drugs can be furthered by adherence to guidelines for methodological standardisation, which are presently under construction by the International Pharmaco-EEG Society (IPEG).

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Negative versus positive allosteric modulation of metabotropic glutamate receptors (mGluR5): indices for potential pro-cognitive drug properties based on EEG network oscillations and sleep-wake organization in rats

Abstract: This functional study differentiates the pharmacology of allosteric blockade of mGluR5 from that of allosteric activation and suggests that mGluR5 blockade enhances sleep and facilitates oscillatory network connectivity, both processes being known to have relevance in cognition processes.

Cited by 28 publications

References 89 publications

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications

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