“The metabotropic glutamate receptor 5 (mGluR5) and the cannabinoid receptor 1 (CB₁) exhibit a functional interaction, as CB₁ regulates pre-synaptic glutamate release and mGluR5 activation increases endocannabinoid synthesis at the post-synaptic site. Since both mGluR5 and CB₁promote neuroprotection, we delineated experiments to investigate a possible link between CB₁ and mGluR5 activation in the induction of neuroprotection using primary cultured corticostriatal neurons. We find that either the pharmacological blockade or the genetic ablation of either mGluR5 or CB₁ can abrogate both CB₁– and mGluR5-mediated neuroprotection against glutamate insult. Interestingly, decreased glutamate release and diminished intracellular Ca²⁺ do not appear to play a role in CB₁ and mGluR5-mediated neuroprotection. Rather, these two receptors work cooperatively to trigger the activation of cell signaling pathways to promote neuronal survival, which involves MEK/ERK1/2 and PI3K/AKT activation. Interestingly, although mGluR5 activation protects postsynaptic terminals and CB₁ the presynaptic site, intact signaling of both receptors is required to effectively promote neuronal survival. In conclusion, mGluR5 and CB₁ act in concert to activate neuroprotective cell signaling pathways and promote neuronal survival.”