title: Metabotropic glutamate receptor 5 as a potential target for smoking cessation.
abstract: Most 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.
  
  
  
  The 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.
  
  
  
  Imaging 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.
  
  
  
  Although 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.
authors.affiliation: Neuropsychopharmacology Lab., Section Pharmacology, Department Diagnostic and Public Health, University of Verona, P.le Scuro 10, 37134, Verona, Italy. cristiano.chiamulera@univr.it.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Chiamulera
authors.affiliation: Neuropsychopharmacology Lab., Section Pharmacology, Department Diagnostic and Public Health, University of Verona, P.le Scuro 10, 37134, Verona, Italy.
authors.forename: Claudio Marcello
authors.initials: CM
authors.lastname: Marzo
authors.affiliation: Division of Neuroscience, University of Dundee Medical School, Mailbox 6, Ninewells Hospital, Dundee, DD1 9SY, UK.
authors.forename: David J K
authors.initials: DJK
authors.lastname: Balfour
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D006801:Humans; D018722:Nicotinic Agonists / Q000008:administration & dosage; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D012646:Self Administration; D012907:Smoking / Q000188:drug therapy / Q000378:metabolism; D016540:Smoking Cessation / Q000379:methods*; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D064529:Receptor, Metabotropic Glutamate 5; D011978:Receptors, Nicotinic
keywords: Cue-evoked relapse; Memory reconsolidation; Negative allosteric modulator; Nicotine self-administration; Smoking cessation; Tobacco addiction; mGluR5