title: The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats.
abstract: Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue- but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence for a causal role of mGluR2 in cue-induced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.
authors.affiliation: Center for Social and Affective Neuroscience, IKE, Linköping University, Linköping, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Augier
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Dulman
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rauffenbart
authors.affiliation: Center for Social and Affective Neuroscience, IKE, Linköping University, Linköping, Sweden.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Augier
authors.affiliation: Innovative Medicines and Early Development Biotech Unit, AstraZeneca Neuroscience, Cambridge, MA, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Cross
authors.affiliation: Center for Social and Affective Neuroscience, IKE, Linköping University, Linköping, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D003216:Conditioning, Operant; D003463:Cues; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage; D005108:Extinction, Psychological / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012008:Recurrence; D012054:Reinforcement, Psychology; D012439:Saccharin / Q000008:administration & dosage; D012646:Self Administration
chemical_list: C000608263:AZD8529; D007211:Indoles; D010069:Oxadiazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D000431:Ethanol; D012439:Saccharin