Association of Long-Term Nicotine Abstinence With Normal Metabotropic Glutamate Receptor-5 Binding

Akkus, Funda; Treyer, Valérie; Johayem, Anass; Ametamey, Simon M.; Mancilla, Baltazar Gomez; Sóvágó, Judit; Buck, Alfred; Hasler, Gregor

doi:10.1016/j.biopsych.2015.02.027

Cited by 36 publications

(51 citation statements)

References 33 publications

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“…These results suggest that the recovery of mGluR5 expression level in the long-term might play a role in relapse. On the other hand, this study also showed that as the density of mGluR5 normalizes after a few years to that of never smokers levels (Akkus et al 2016). Importantly, mGluR5 binding did not appear to be a causal factor for successful abstinence duration, suggesting that mGluR5 down-regulation is a timedependent a-posteriori consequence of effects and cessation to/of nicotine exposure, and not an a priori mechanism that determines the duration of abstinence and the risk of an earlier withdrawalassociated relapse.…”

Section: Page 17 Of 34 Psychopharmacologymentioning

confidence: 52%

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

2016

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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.

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Section: Page 17 Of 34 Psychopharmacologymentioning

confidence: 52%

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

2016

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“…In a previous study we found a marked global reduction in mGluR5 in smokers and recent exsmokers (average abstinence duration of 25 weeks) (Akkus et al, 2013). In a follow-up study we found normal mGluR5 DVR in long-term ex-smokers and a trend for a relationship between low mGluR5 DVR and the risk of relapse (Akkus et al, 2015). Together, these data suggest that the down-regulation of mGluR5 is a mechanism underlying nicotine dependence and the high risk of relapse in ex-smokers.…”

Section: Discussionmentioning

confidence: 65%

“…In rats, typical and atypical antipsychotics increased mGluR5 mRNA expression (Iasevoli et al, 2010), while other studies did not show changes in mGluR5 binding following treatment with antipsychotic drugs, in either animals or human postmortem tissue . In previous studies, we have demonstrated that smoking is associated with a marked global reduction in mGluR5 DVR (Akkus et al, 2013;Akkus et al, 2015). This is a potentially relevant finding because 60%-90% of individuals with schizophrenia smoke (Chapman et al, 2009), and they usually smoke more heavily and experience more difficulty quitting smoking than do smokers without schizophrenia (Tidey et al, 2005;Wing et al, 2012).…”

Section: Introductionmentioning

confidence: 78%

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Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

Akkus

Treyer

Ametamey

et al. 2017

Schizophrenia Research

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The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status. Binding to mGluR5 was determined using positron emission tomography and [ 11 C]ABP688, which binds to an allosteric site with high selectivity. DVR in the 15 individuals with schizophrenia did not differ from that of the 15 controls. In both groups, smoking was associated with marked global reductions in mGluR5 availability (on average 23.8%). In nonsmoking subjects with schizophrenia, there was a positive correlation between mGluR5 DVR in the medial orbitofrontal cortex and the use of antipsychotic drugs (r = 0.9, p =0.019). Because antipsychotic drugs such as clozapine appeared to have indirect effects on mGluR5 signaling, our findings may be clinically relevant. They also provide promising leads for elucidating the high comorbidity between schizophrenia and tobacco addiction. Low mGluR5 DVR in smokers my represent a risk factor for schizophrenia. Alternatively, smoking may counteract the potential upregulation of mGluR5 by antipsychotic drugs.

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“…Another study demonstrated that MPEP decreased nicotine seeking in rats (Palmatier et al, 2008). It is important to note that long-term use ex-smokers had higher mGluR5 binding as compared to recent use ex-smokers in thalamus and frontal cortex suggesting that mGluR5 is an important biomarker for nicotine dependence (Akkus et al, 2015). Furthermore, studies have demonstrated that mGluR5 or mGluR1 antagonists are able to reduce cue-induced reinstatement of nicotine self-administration in rats (Bespalov et al, 2005, Dravolina et al, 2007).…”

Section: Role Of Glutamate Receptors In Nicotine Dependencementioning

confidence: 99%

Targeting glutamate homeostasis for potential treatment of nicotine dependence

Alasmari

Al‐Rejaie

AlSharari

et al. 2016

Brain Research Bulletin

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Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with downregulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence.

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Association of Long-Term Nicotine Abstinence With Normal Metabotropic Glutamate Receptor-5 Binding

Cited by 36 publications

References 33 publications

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

Targeting glutamate homeostasis for potential treatment of nicotine dependence

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