The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on the stimulation of dopamine release evoked by nicotine in the rat brain

Tronci, Valeria; Balfour, David J.K.

doi:10.1016/j.bbr.2010.12.024

Cited by 21 publications

(30 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Contributions of direct monoamine reuptake transporter inhibition to the accumbal DA elevation can be excluded in view of basimglurant's lack of activity on these transporters. Previous studies showed that MPEP had no effect on DA levels in the nucleus accumbens, but it blocked nicotine-evoked accumbal DA release (Tronci and Balfour, 2011) and dampened amphetamine-triggered DA outflow in the striatum (Tokunaga et al, 2009). The discrepancy between the current study and the previous report on accumbal DA levels might be due to the higher in vivo potency and longer half-life of basimglurant compared with MTEP.…”

Section: Discussioncontrasting

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

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

View full text Add to dashboard Cite

show abstract

“…By contrast, repetitive exposure to self-administered nicotine results in sensitisation of the DA response to the drug in both subdivisions of the accumbens (Lecca et al 2006). Tronci and Balfour (2011) showed that pretreating rats with the mGluR5 antagonist, MPEP, 30 minutes prior to a challenge dose of nicotine attenuated the increase in DA overflow in the accumbal shell in a dose-dependent way, complete blockade of the response being achieved with a dose of 5mg/kg of the antagonist ( Figure 1A). MPEP also attenuated the increase in DA overflow evoked by a nicotine injection in the accumbal core of rats that had been sensitised to the drug with daily injections of nicotine ( Figure 1B).…”

Section: The Role Of Mglur5 Receptors In the Neural Responses To Nicomentioning

confidence: 99%

“…Significantly different from rats pretreated with MPEP on the test day (2.5 mg/kg) ++p<0.01; +++p<0.001; significantly different from rats pretreated MPEP (5.0 mg/kg) on the test day *p<0.05; ***p<0.001. Modified from Tronci and Balfour (2011).…”

Section: Figurementioning

confidence: 99%

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

2016

View full text Add to dashboard Cite

RationaleMost habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor.Relapse rates, however, remain high and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. ObjectiveThe purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. ResultsImaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. ConclusionsAlthough mGluR5 NAMs attenuate most of the key facets of nicotine dependence they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many "off target" effects to be used clinically. However newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence.

show abstract

“…Extensive evidence implicates mGluR 5 and other postsynaptic G q -coupled receptors in the activation of diacylglycerol lipase a involved in 2-AG formation (Jung et al, 2005), although the relative influence of volitional vs forced nicotine administration on these and related G qcoupled receptors have not been investigated. It is conceivable, however, that diminished 2-AG formation has a role in the attenuation of nicotine SA behavior induced by mGluR 5 antagonists (D'Souza and Markou, 2011;Tronci and Balfour, 2011).…”

Section: Endocannabinoid Levels Following Nicotine Exposure Mw Buczynmentioning

confidence: 99%

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

Buczynski

Polis

Parsons

2012

Neuropsychopharmacol

View full text Add to dashboard Cite

Cannabinoid-1 receptors (CB 1 ) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB 1 (by AEA and 2-AG) and non-CB 1 (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine.

show abstract

The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on the stimulation of dopamine release evoked by nicotine in the rat brain

Cited by 21 publications

References 20 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

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

Contact Info

Product

Resources

About