Premium
An investigation of metabotropic glutamate receptor 5 negative allosteric modulators in physiological and behavioral indicators of anxiety and cognition in rodents
Author(s) -
Moon Joshua,
McGinnis Dina,
Smith Deborah L,
Graf Radka,
Hughes Zoe,
Grimwood Sarah,
Miller Emily,
Trapa Patrick,
Shaffer Christopher L,
Siok Chester J
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1099.4
Subject(s) - anxiolytic , metabotropic glutamate receptor 5 , metabotropic glutamate receptor , neuroscience , hippocampal formation , allosteric regulation , glutamate receptor , elevated plus maze , psychology , metabotropic receptor , allosteric modulator , hippocampus , anxiety , chemistry , pharmacology , receptor , medicine , psychiatry , biochemistry
Negative allosteric modulators (NAMs) of the metabotropic glutamate receptor type 5 (mGluR5) have been proposed as potential anxiolytic therapeutics. However, evidence from rodent studies suggests that at high doses they may also cause cognitive disruption (Ballard et al., 2005). The stimulated hippocampal theta EEG model in rats has been proposed to be predictive of both anxiolytic activity and cognitive enhancement or disruption (McNaughton et al., 2007). We used this assay to test three mGluR5 NAMs (AFQ056 and two novel, structurally distinct compounds) for signs of anxiolytic activity and cognitive disruption. These studies were supported by rat in vivo receptor occupancy (RO), mouse stress‐induced hyperthermia (SIH) to assess anxiety, and rat radial arm maze (RAM) to evaluate spatial working memory. Consistent with predicted anxiolytic activity, all three compounds lowered stimulated theta frequency without affecting theta power or overt oscillatory activity at RO levels which reduced SIH. At ≥80% RO, which afforded RAM disruptions, theta power was lowered or disrupted. While previous studies of stimulated hippocampal theta have compared class effects of anxiolytic or cognitively impairing agents, this is the first study linking RO to both electrophysiological properties and behavioral effects, further demonstrating the value of the stimulated theta assay for characterizing novel mechanisms. Sponsored by Pfizer, Inc.