title: Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats.
abstract: Numerous medication development strategies seek to decrease nicotine consumption and prevent relapse to tobacco smoking by blocking glutamate transmission. Decreasing glutamate release by activating presynaptic inhibitory metabotropic glutamate (mGlu)2/3 receptors inhibits the reinforcing effects of nicotine and blocks cue-induced reinstatement of nicotine-seeking behavior in rats. However, the relative contribution of mGlu2 receptors in nicotine dependence is still unknown.
  
  
  
  The present study evaluated the role of mGlu2 receptors in nicotine-taking and nicotine-seeking behavior using the novel, relatively selective mGlu2 positive allosteric modulators (PAMs) AZD8418 and AZD8529.
  
  
  
  Acute treatment with AZD8418 (0.37, 1.12, 3.73, 7.46, and 14.92 mg/kg) and AZD8529 (1.75, 5.83, 17.5, and 58.3 mg/kg) deceased nicotine self-administration and had no effect on food-maintained responding. Chronic treatment with AZD8418 attenuated nicotine self-administration, but tolerance to this effect developed quickly. The inhibition of nicotine self-administration by chronic AZD8529 administration persisted throughout the 14 days of treatment. Chronic treatment with either PAMs inhibited food self-administration. AZD8418 (acute) and AZD8529 (acute and subchronic) blocked cue-induced reinstatement of nicotine- and food-seeking behavior.
  
  
  
  These findings indicate an important role for mGlu2 receptors in the reinforcing properties of self-administered nicotine and the motivational impact of cues that were previously associated with nicotine administration (i.e., cue-induced reinstatement of nicotine-seeking behavior). Thus, mGlu2 PAMs may be useful medications to assist people to quit tobacco smoking and prevent relapse.
authors.affiliation: Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA.
authors.forename: Manoranjan S
authors.initials: MS
authors.lastname: D'Souza
authors.affiliation: Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Niño
authors.affiliation: Present address: Sage Therapeutics, Cambridge, MA, 02142, USA.
authors.forename: James
authors.initials: J
authors.lastname: Doherty
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, 02139, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Cross
authors.affiliation: Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA. amarkou@ucsd.edu.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy*
chemical_list: C000608263:AZD8529; D007211:Indoles; D010069:Oxadiazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D009538:Nicotine
keywords: Chronic treatment; Metabotropic glutamate receptor; Nicotine; Reinstatement; Self-administration