Allosteric Modulation of Metabotropic Glutamate Receptor 5 (Mglur5) In Treatment-Resistant Depression: Electrophysiological and Behavioral Correlates in Rodent Models

Treatment-resistant depression (TRD) affects a substantial proportion of patients with major depressive disorder and highlights the need for therapeutic strategies beyond traditional monoaminergic approaches. Metabotropic glutamate receptor 5 (mGluR5), a critical regulator of glutamatergic neurotransmission, has gained attention as a potential target, with allosteric modulation offering refined control without direct orthosteric receptor activation or blockade. In the present study, the effects of the mGluR5 negative allosteric modulator basimglurant were evaluated in a rodent model of TRD. Male Wistar rats (n = 60) were exposed to chronic unpredictable stress for 21 days to induce depression-like phenotypes and subsequently treated with basimglurant (0.1–3 mg/kg, p.o.) or vehicle. Behavioral despair was assessed using the forced swim test and tail suspension test, while synaptic plasticity was examined through electrophysiological recording of hippocampal long-term potentiation. Neurotrophic changes were evaluated by immunohistochemical analysis of brain-derived neurotrophic factor expression in the hippocampus. Basimglurant produced a dose-dependent reduction in immobility time in both behavioral tests, significantly restored long-term potentiation amplitude compared with stressed controls, and markedly increased the number of BDNF-positive neurons in the CA1 region of the hippocampus, without inducing motor impairments. These findings demonstrate that negative allosteric modulation of mGluR5 alleviates TRD-like behaviors in rodents, potentially through enhancement of synaptic plasticity and neurotrophic signaling, and supports mGluR5 NAMs as promising candidates for the treatment of TRD.