CRIP1a switches cannabinoid receptor agonist/antagonist-mediated protection from glutamate excitotoxicity

► CB 1 is expressed in embryonic cortical neurons in vitro and in vivo. ► CRIP1a mRNA and protein are expressed in cortical neurons in vitro and in vivo. ► CRIP1a, CB 1 agonist, and CB 1 antagonist did not alter basal neuronal cell death. ► CRIP1a reversed CB 1 agonist mediated neuroprotection from glutamate excitotoxicity. ► CRIP1a conferred to a CB 1 antagonist neuroprotection from glutamate excitotoxicity. A shared pathology among many neurological and neurodegenerative disorders is neuronal loss. Cannabinoids have been shown to be neuroprotective in multiple systems. However, both agonists and antagonists of the CB 1 cannabinoid receptor are neuroprotective, but the mechanisms responsible for these actions remain unclear. Recently a CB 1 receptor interacting protein, CRIP1a, was identified and found to alter CB 1 activity. Here we show that in an assay of glutamate neurotoxicity in primary neuronal cortical cultures CRIP1a disrupts agonist-induced neuroprotection and confers antagonist-induced neuroprotection.