Role of AMPA receptor stimulation and TrkB signaling in the antidepressant-like effect of ketamine co-administered with a group II mGlu receptor antagonist, LY341495, in the forced swim test in rats.

Ketamine produces rapid antidepressant effects in people with depression. In rats, a drug called LY341495, which blocks group II metabotropic glutamate receptors, also shows rapid and lasting antidepressant-like activity and can boost the effect of a low dose of ketamine without side effects. This study examined how AMPA receptors and TrkB receptors contribute to the antidepressant-like effects of ketamine (3 mg/kg) given together with LY341495 (0.1 mg/kg) in the forced swim test in rats, measured 40 minutes, 3 hours, and 24 hours after administration. Blocking AMPA receptors with NBQX (10 mg/kg) reversed the antidepressant effect at all time points, while blocking TrkB receptors with ANA-12 blocked the effect only at 3 hours.

Study at a glance

Abstract

Ketamine has been shown to induce a rapid antidepressant effect on patients with depression. In many animal models, both rapid and sustained antidepressant activities were also found in response to an antagonist of group II metabotropic glutamate receptors, LY341495, and its mechanism of action seemed to be similar in many ways to the action of ketamine. It has also been found that LY341495 enhanced the antidepressant-like activity of sub-effective doses of ketamine in rats without inducing adverse effects. Here, we investigated the role of AMPA receptor and TrkB receptor activation in the antidepressant-like effects of ketamine (3 mg/kg) co-administered with LY341495 (0.1 mg/kg), in the forced swim test in rats, at three time points (40 min, 3 h and 24 h) after joint administration of the tested compounds. It was found that the AMPA receptor antagonist NBQX (10 mg/kg) reversed the antidepressant effect of ketamine co-administered with LY341495 at all tested time points, whereas the TrkB receptor antagonist ANA-12 contributed to blockade of the effect of ketamine and LY341495 3 h after their joint administration. These results indicate that activation of AMPA receptor and BDNF-related signaling may play a role in the mechanism of antidepressant action of ketamine co-administered with LY341495.