mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure

A single injection of the experimental compound LY341495, which blocks mGluR2/3 receptors, rapidly and lastingly reversed anhedonia—a core symptom of depression—in rats subjected to chronic unpredictable stress. The effect appeared within one to two days and persisted for at least ten days, a timeline comparable to the rapid antidepressant action of ketamine but without ketamine's side effects and abuse potential. Typical antidepressants require weeks to produce a response. The findings suggest that mGluR2/3 antagonists may offer a safer alternative for fast-acting depression treatment.

Study at a glance

Abstract

BACKGROUND: Depression is a prevalent neuropsychiatric disorder that affects an estimated 350 million people worldwide. Currently available treatments for depression are lacking in both speed of onset and efficacy. Recent pharmacological efforts have targeted the glutamatergic neurotransmitter system using the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine to produce rapid and robust antidepressant effects, however the widespread clinical use of ketamine is limited due to side effects and abuse liability. More recently, work evaluating metabotropic mGluR2/3 receptor antagonists has demonstrated many similarities with ketamine. METHODS: Male, Sprague-Dawley rats were exposed to a chronic unpredictable stress paradigm, which produces decreased sucrose preference, a measure of anhedonia. Rats were then treated with vehicle or a single injection of the mGluR2/3 antagonist LY341495 (3 mg/kg, i.p.) and tested at 24 hrs, 48 hrs or 10 days after a single treatment. RESULTS: We demonstrate that a single treatment with LY341495 produces a rapid (within 1-2 days) and long-lasting (10 days) reversal of anhedonia caused by chronic unpredictable stress in rats. This model provides a rigorous test of rapid-acting agents as typical antidepressants require several weeks of treatment to produce a response. CONCLUSIONS: These data suggest that LY341495 has the ability to produce rapid and robust antidepressant effects similar to ketamine. Together, the results highlight the potential for similar compounds to produce rapid and lasting efficacy for the treatment of depression.