title: The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior.
abstract: Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior.
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Heidelberg, Germany. nazzareno.cannella@zi-mannheim.de
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Cannella
authors.forename: Briac
authors.initials: B
authors.lastname: Halbout
authors.forename: Stefanie
authors.initials: S
authors.lastname: Uhrig
authors.forename: Lionel
authors.initials: L
authors.lastname: Evrard
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
authors.forename: Corrado
authors.initials: C
authors.lastname: Corti
authors.forename: Veronique
authors.initials: V
authors.lastname: Deroche-Gamonet
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D012646:Self Administration
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D003042:Cocaine