title: Pharmacological interference with metabotropic glutamate receptor subtype 7 but not subtype 5 differentially affects within- and between-session extinction of Pavlovian conditioned fear.
abstract: Fear extinction is defined as the attenuation of a conditioned-fear memory by re-exposing animals to the conditioned stimulus without the aversive stimulus. This process is known to be effectively enhanced via administration of D-cycloserine (DCS), a partial NMDA-receptor agonist. However, other glutamatergic mechanisms, such as interference with metabotropic glutamate receptor (mGluR) subtypes 5 and 7 in the extinction of aversive memories are insufficiently understood. Using the allosteric mGluR5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), and DCS for comparison, we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influenced within- and between-session conditioned-fear extinction training and extinction retention in rats. We show that when injected before extinction training, mGluR7 activation with AMN082 enhanced freezing and thereby attenuated within-session fear extinction, whereas both DCS and the mGluR5 receptor antagonist MPEP had no effect on this process. However, these differential drug effects were not long lasting, as no difference in extinction retention were observed 24 h later. Therefore, we assessed whether the compounds affect 24 h consolidation of extinction training following incomplete extinction training (between-session extinction). Similar to DCS, AMN082- but not MPEP-treated rats showed facilitated extinction retention, as exhibited by decreased freezing. Finally, using fluoxetine, we provide evidence that the effect of AMN082 on between-session extinction retention is most likely not via increasing 5-HT transmission. These findings demonstrate that mGluR7 activation differentially modulates conditioned-fear extinction, in dependence on the protocol employed, and suggests drugs with AMN082-like mechanisms as potential add-on drugs following exposure-based psychotherapy for fear-related human disorders.
authors.affiliation: University of Regensburg, Faculty of Biology and Preclinical Medicine, Regensburg, Germany.
authors.forename: Iulia
authors.initials: I
authors.lastname: Toth
authors.forename: Monika
authors.initials: M
authors.lastname: Dietz
authors.forename: Daniel
authors.initials: D
authors.lastname: Peterlik
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Huber
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.forename: Inga D
authors.initials: ID
authors.lastname: Neumann
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flor
authors.forename: David A
authors.initials: DA
authors.lastname: Slattery
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D001559:Benzhydryl Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005473:Fluoxetine; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D017367:Selective Serotonin Reuptake Inhibitors; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; C102719:metabotropic glutamate receptor 7; C121465:6-methyl-2-(phenylethynyl)pyridine