Anxiolytic-like effects of an mGluR 5 antagonist and a mGluR 2/3 agonist, and antidepressant-like effects of an mGluR 7 agonist in the chick social separation stress test, a dual-drug screening model of treatment-resistant depression

Modulation of glutamate receptors has demonstrated anxiolytic and/or antidepressant effects in rodent stress models. The chick social-separation stress paradigm exposes socially raised aves to an isolation stressor which elicits distress vocalizations (DVocs) in an attempt to re-establish contact. The model presents a state of panic during the first 5 min followed by a state of behavioral despair during the last 60 to 90 min. Making it useful as a dual anxiolytic/antidepressant screening assay. Further research has identified the Black Australorp strain as a stress-vulnerable, treatment-resistant, and ketamine-sensitive genetic line. Utilizing this genetic line, we sought to evaluate modulation of glutamatergic receptors for potential anxiolytic and/or antidepressant effects. Separate dose-response studies were conducted for the following drugs: the AMPA PAM LY392098, the mGluR 5 antagonist MPEP, the mGluR 2/3 agonist LY404039, the mGluR 2/3 antagonist LY341495, and the mGluR 7 agonist AMN082. The norepinephrine α² agonist clonidine and the NMDA antagonist ketamine were included as comparison for anxiolytic (anti-panic) and antidepressant effects, respectively. As in previous studies, clonidine reduced DVoc rates during the first 5 min (attenuation of panic) and ketamine elevated DVoc rates (attenuation of behavioral despair) during the last 60 min of isolation. The mGluR 2/3 agonist LY404039 and the mGluR 5 antagonist MPEP decreased DVoc rates during the first 5 min of isolation indicative of anxiolytic effects like that of clonidine while the mGluR 7 agonist AMN082 elevated DVoc rates in the later hour of isolation, representative of antidepressant effects like that of ketamine. Collectively, these findings suggest that certain glutamate targets may be clinically useful in treating panic disorder and/or treatment-resistant depression.

Ionotropic glutamate receptors; Metabotropic glutamate receptors; Panic disorder; Treatment-resistant depression.