title: The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats.
abstract: Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 3'-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, 92093-0603, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Jin
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Robert
authors.initials: R
authors.lastname: Ardecky
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002461:Cell Line, Transformed; D003042:Cocaine / Q000008:administration & dosage*; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration / Q000379:methods; D013997:Time Factors
chemical_list: D000596:Amino Acids; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018765:Dopamine Uptake Inhibitors; D018690:Excitatory Amino Acid Agonists; D007189:Indans; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C522461:biphenyl-indanone A; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid; D003042:Cocaine