title: The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear.
abstract: The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.
authors.affiliation: Behavioural Neuroscience Division,Florey Institute of Neuroscience and Mental Health,VIC,Australia.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Handford
authors.affiliation: Behavioural Neuroscience Division,Florey Institute of Neuroscience and Mental Health,VIC,Australia.
authors.forename: Shawn
authors.initials: S
authors.lastname: Tan
authors.affiliation: Behavioural Neuroscience Division,Florey Institute of Neuroscience and Mental Health,VIC,Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.affiliation: Behavioural Neuroscience Division,Florey Institute of Neuroscience and Mental Health,VIC,Australia.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects*; D003463:Cues; D003523:Cycloserine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D005239:Fear / Q000187:drug effects*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018683:Excitatory Amino Acid Agents; D011725:Pyridines; D013844:Thiazoles; D003523:Cycloserine