Cannabinoid CB₁ Receptor Activation Mitigates <i>N</i>-Methyl-d-aspartate Receptor-Mediated Neurotoxicity

Alzheimer's disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB1 receptors (CB1Rs) and N-methyl-d-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB1R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB1R-mediated cAMP inhibition, while CB1R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor-receptor interactions with functional consequences. Complexes of CB1Rs and N1 subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to A beta 1-42 and in cells derived from the APPSw/Ind AD model mice. However, upregulation did not always correlate with stronger CB1R-NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB1R activation confers neuroprotection: It rescues neurite loss induced by NMDA and A beta 1-42, highlighting the therapeutic potential of modulating CB1R-NMDAR interactions. These findings support a model in which CB1R-NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.