426. THE MGLUR2/3 ANTAGONIST ENHANCES THE BEHAVIORAL AND CELLULAR ANTIDEPRESSANT-LIKE EFFECTS OF PSILOCYBIN AND SCOPOLAMINE

Hallucinogens from different classes, such as scopolamine and psilocybin, show rapid antidepressant effects that are enhanced by blocking group II metabotropic glutamate (mGlu2/3) receptors. In mice, scopolamine reversed depressive-like behaviors induced by chronic mild stress, and a selective M1 muscarinic antagonist produced dose-dependent antidepressant effects potentiated by an mGlu2 receptor negative allosteric modulator. Scopolamine increased extracellular dopamine, serotonin, and glutamate in the frontal cortex, while the mGlu2 modulator had opposite effects on glutamate. A low dose of the mGlu2/3 antagonist LY341495 boosted the antidepressant effect of low-dose psilocybin in the tail suspension test, with rapid onset and long duration, while also reducing hallucinogenic-like head twitch responses. Combined targeting of these systems may allow lower doses and fewer side effects while maintaining antidepressant efficacy.

Study at a glance

Abstract

Abstract Background Numerous data indicates that hallucinogens from various groups such as ketamine, scopolamine or psilocybin exert rapid antidepressant effects in both preclinical and clinical studies. Group II glutamate (mGlu) metabotropic receptor antagonists also show rapid antidepressant efficacy in animal studies, moreover we have shown that mGluR2/3 antagonist, LY341495 is able to enhance antidepressant-like action of ketamine. Aims & Objectives The aim of the present study was to investigate in a more detailed manner the mechanisms of interactions between scopolamine or psilocybin and mGlu2/3 agents. Method The behavioral tests including the forced swimming test (FST), tails suspension test (TST), the chronic unpredictable mild stress model of depression (CUMS) were applied. Locomotor activity (LA) was tested to assess any non-specific effects. In vitro receptor interaction assays with T-REx 293 cells expressing one or both labeled receptors were also conducted. The electrophysiological and in vivo release effects were also investigated. Results In the CUMS model of depression in male C57BL/6J mice subchronic scopolamine, (administered at a dose of 0.3 mg/kg for four consecutive days), significantly reversed the CUMS-induced depressive-like behaviors, such as apathy, anhedonia, and behavioral despair. Moreover, a selective M1 muscarinic receptor antagonist VU0255035 produced a dose dependent antidepressant effect which were potentiated by a low dose of mGlu2 receptor negative allosteric modulator (NAM) VU60001966. Furthermore, scopolamine and VU6001966 increased extracellular dopamine and serotonin levels in the frontal cortex (FCx) without affecting GABA levels. Scopolamine also increased glutamate level, whereas VU6001966 had the opposite effect. A low dose of LY341495 which is inactive by itself enhances significantly antidepressant effects of low dose of psilocybin in TST in naive mice. The antidepressant effect was rapid (1h) and long-lasting (3 and 7 days). Changes in the immobility time were independent of spontaneous LA of mice. Interestingly, co-administration of LY341495 affects also psilocybin induced head twitch response that refers to hallucinogenic-like behavior and may indicate a potential reduction of side effects. Synergistic effect of Psilocin (1uM) and LY341495 (200nM) on frequency sEPSC in the mouse FCx were seen. Lastly - behavioral outcomes were corelated with changes in synaptic proteins level in the pFCx and hippocampus, structures related to synaptic plasticity, a fingerprint of AD-like activity. Discussion & Conclusions The results show that hallucinogens of different classes exert an antidepressant effect which is potentiated by mGlu2/3 receptor antagonists or mGlu2 receptor NAMs. The mechanism of this enhancement appears to be through increased glutamate release and activation of a cascade of neurogenesis-related elements. A combined targeting two different neurotransmission systems may allow to lover the doses on interacting agents and reduce adverse effects while the antidepressant efficacy is maintained. Acknowledgements This research was funded by National Science Centre, Poland, grants number 2020/37/B/NZ7/03499 and 2023/49/B/NZ7/02978 given to Andrzej Pilc.