Metabotropic glutamate receptor 5 as a potential target for smoking cessation

Abstract

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.

The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats

“…GluA1 has been shown to be important for memory retrieval (Clem & Huganir, 2010;Monfils et al, 2009) in a way dissociable from its role in destabilization (Milton et al, 2013), suggesting that these two processes may occur in parallel via two separate glutamatergic networks in Amy (Lee & Flavell, 2014;Milton et al, 2013). Although there is a limited literature on Group I metabotropic glutamate receptors and memory reconsolidation (Gieros, Sobczuk, & Salinska, 2012;Salinska, 2006), we have recently proposed that Group I subtype mGluR5 is involved in memory reconsolidation and that mGluR5 antagonism may act as inhibitor based on the role played by mGluR5 in the modulation of glutamatergic transmission (Chiamulera, Marzo, & Balfour, 2017). Moreover, glutamate receptors GluN2B, GluA1 and mGluR5 have been reported to be involved in different forms of metaplasticity (Bortolotto et al, 2005;Tenorio et al, 2010;Yang et al, 2012; for reviews, see Abraham, 2008;Hulme et al, 2013;Marton, Hussain Shuler, & Worley, 2015).…”

Computational Systems Pharmacology-Target Mapping for Fentanyl-Laced Cocaine Overdose

“…[6][7][8][9][10][11] Of note, D3R and μOR belong to class A of G-protein coupled receptors (GPCRs), which is the largest family of trans-membrane proteins, targeted by 30−40% of marketed drugs. 12 Moreover, ligands of other GPCRs are also reported to show potential therapeutic effects regarding drug abuse, including muscarinic acetylcholine receptor M4, 13 γ-amino-butyric acid type B receptor (GABAB), [14][15][16][17] metabotropic glutamate receptor 2 (mGluR2), [18][19][20] metabotropic glutamate receptor 5 (mGlu5), [21][22][23][24][25] trace amine-associated receptor 1 (TAAR1), [26][27][28][29] adenosine A2A receptor (A2aR), [30][31][32] cannabinoid 1-receptor (CB1R), 33,34 and cannabinoid 2-receptor (CB2R). 3,[35][36][37] Especially, CB2R, a member of GPCRs that is expressed in both peripheral tissues and brain, has been reported to produce a large therapeutic effect when treated with its agonists.…”

The role of the metabotropic glutamate receptor 5 in nicotine addiction

“…Several preclinical studies have found that nicotine increases glutamatergic transmission through activation of nicotinic acetylcholine receptor (nAChRs) located on glutamatergic afferents in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) 14 (see Figure 1 for depiction of this action). Furthermore, long-term nicotine exposure could cause changes in dopamine and glutamate systems 8 For example, it was found that nicotine injections enhanced the brains reward function in rats as measured through intracranial self-administration 15 . Nicotine dependence is the result of a positive effect of nicotine, specifically, it induces a dopamine (DA) increase in NAc.…”

“…110 It further illustrates the accumulating evidence suggesting that mGluR5 is significant in nicotine addiction. Accepted Manuscript: Authors' Copy 8 mGluR5 and nicotine addiction 11,13,15 . In an mGluR5 knock out model study, it was suggested that this receptor is implicated in anhedonia and somatic signs of nicotine withdrawal 27 .…”

“…with dopamine D1/D2, NMDA, adenosine A2, and GABA receptors 11,13,15 . The mGlu5 receptor was co-localised with dopamine and adenosine receptors in the striatum, including the NAc, where they are involved in the regulation of dopaminergic neurotransmission 15,25 .…”