Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant effects in rats: Role of brain-derived neurotrophic factor

Liu, C.Y.; Jiang, Xiaohui; Zhu, Yu; Wei, Danian

doi:10.1016/j.neuroscience.2012.08.010

Cited by 34 publications

(21 citation statements)

References 29 publications

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“…These results are particularly relevant as the CMS method is considered a disease model for depression with good face-validity (Moreau, 2002;Nestler and Hyman, 2010), reflecting several key aspects of the human condition including a reduced hedonic drive, altered sleep/wake pattern, and endocrine changes in the hypothalamic-pituitary-adrenal axis (Moreau et al, 1995;Grippo et al, 2005). The dose-dependent reduction of immobility time by basimglurant in the FST, a screening procedure used for the profiling of antidepressants (Nestler and Hyman, 2010), is in agreement of what has been reported for other mGlu5 NAMs (Liu et al, 2012;Hughes et al, 2013). Moreover, fMRI recordings Basimglurant, an mGlu5 NAM in Development for Depression Fig.…”

Section: Discussionsupporting

confidence: 74%

“…Thus, it was not surprising to see that mGlu5 inhibitors have behavioral effects in rodents in procedures that are used to identify potential antidepressant and related antianxiety drugs. For example, MPEP corrected escape behavior in a learned helplessness procedure while it increased levels of brain-derived neurotropic factor in the hippocampus (Liu et al, 2012); brain-derived neurotrophic factor has long been linked with affective behavior and depression (Nestler et al, 2002;Monteggia, 2011). MPEP and MTEP also decreased immobility in a mouse forced-swim test (FST); the effect of MPEP in the FST was not observed in mGlu5 knockout mice, confirming that the antidepressant-like effect was indeed mediated by mGlu5 receptors (Li et al, 2006).…”

Section: Introductionmentioning

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: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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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“…It was further demonstrated that administration of SKF 83959, an agonist for the Gq-coupled D5R and D1-D2 receptor heteromer, had differential effects in juvenile and adults rats and could effectively normalize the differences in BDNF-TrkB signaling observed in the juvenile animals to adult levels. Although the present discussion will focus on BDNF regulation by dopamine, it is important to note that a number of neurotransmitter systems may have contributed to the present findings of differential basal BDNF expression in juvenile rats, as serotonin [44], norepinephrine [45], glutamate [46], and GABA [47] have also been shown to be involved in the neuronal regulation of BDNF. Furthermore, while the regional differences in protein expression will be discussed, it is important to note that the effects reported in the present study may not be mutually exclusive as interactions between the striatum and PFC, both of which are components of the mesocorticolimbic circuitry, are well characterized.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Brain-Derived Neurotrophic Factor Signaling in the Nucleus Accumbens of Juvenile Rats

Perreault¹,

Fan²,

O’Dowd³

et al. 2013

Dev Neurosci

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Brain-derived neurotrophic factor (BDNF) signaling through its receptor, tropomyosin receptor kinase B (TrkB), plays a critical role in neural plasticity and its dysregulation in striatum and prefrontal cortex (PFC) has been implicated in the etiology of mental health disorders such schizophrenia and drug addiction. In the present study, we characterized age-dependent differences in BDNF signaling and TrkB expression within the nucleus accumbens (NAc), caudate putamen (CP) and PFC in rats and determined the effects of administration of the dopamine agonist, SKF 83959, which activates the Gq-coupled dopamine receptors, the dopamine D5 receptor and the D1-D2 receptor heteromer. As proBDNF binds with high affinity to the p75 neurotrophin receptor (p75NTR), expression levels of these proteins were also assessed. The present findings showed that juvenile rats (aged 26-28 days) exhibited significantly elevated basal BDNF expression and activation of full-length TrkB (TrkBfull) in NAc compared to their adult counterparts, as evidenced by increased TrkBfull phosphorylation. These changes were concomitant with an increase in the relative expression of TrkBfull compared to the truncated isoform, TrkB.T1, in NAc and CP. Conversely, in PFC the basal expression of BDNF in juvenile rats was significantly lower than in adult rats with an elevated relative expression of TrkBfull. Acute administration of SKF 83959 to juvenile rats abolished the age-dependent differences in BDNF expression in NAc and PFC, and in the relative expression of TrkBfull in NAc and CP. Together these findings indicate that the expression and/or signaling of BDNF and TrkB in striatum and PFC of juvenile rats is fundamentally different from that of adult rats, a finding that may have implications in neuropsychiatric disorders that exhibit age-dependent susceptibility such as schizophrenia and drug addiction.

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“…Such a hypothesis can help understand within the frame of the current hypotheses of depression why the mGlu5 NAMs MPEP and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl) pyridine can produce antidepressant effects in the forced swim test [24]. Their antidepressant potential was also supported by the ability of MPEP to increase hippocampal BDNF levels, a marker of antidepressant activity [25,26].…”

Section: Introductionmentioning

confidence: 93%

Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5

Fuxé

Borroto-Escuela

2015

Expert Opinion on Investigational Drugs

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The antidepressant activity of basimglurant may be related to a preferential reduction of mGlu5 receptor signaling in distinct populations of cortical limbic GABA interneurons causing disinhibition of discrete glutamate neuronal networks in brain circuits of mood and emotion. Basimglurant's removal of mGlu5 receptor induced inhibition of D2 receptor signaling in A2A-D2-mGlu5 heteroreceptor complexes of ventral striato-pallidal GABA neurons mediating anti-reward may also play a role. Basimglurant is a highly promising antidepressant drug now in clinical development for depression. However, further clinical trials are highly warranted.

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Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant effects in rats: Role of brain-derived neurotrophic factor

Cited by 34 publications

References 29 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

Enhanced Brain-Derived Neurotrophic Factor Signaling in the Nucleus Accumbens of Juvenile Rats

Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5

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