title: mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.
abstract: Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study, the authors investigated the effects of the Type-5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction-training sessions required to meet extinction criteria. Pre- or postextinction-training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self-administration and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction.
authors.affiliation: Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, SC, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cleva
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hicks
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gass
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Wischerath
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Plasters
authors.forename: John J
authors.initials: JJ
authors.lastname: Widholm
authors.forename: M Foster
authors.initials: MF
authors.lastname: Olive
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D003042:Cocaine / Q000008:administration & dosage*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000096:biosynthesis* / Q000502:physiology; D012646:Self Administration
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; C578937:Grm5 protein, rat; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D003042:Cocaine