Differential contribution of CB1, CB2, 5-HT1A, and PPAR-γ receptors to cannabidiol effects on ischemia-induced emotional and cognitive impairments

An ever-increasing body of preclinical studies has shown the multifaceted neuroprotective profile of cannabidiol (CBD) against impairments caused by cerebral ischemia. In this study, we have explored the neuropharmacological mechanisms of CBD action and its impact on functional recovery using a model of transient global cerebral ischemia in mice. C57BL/6J mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min and received vehicle or CBD (10 mg/Kg) 0.5 h before and 3, 24, and 48 h after reperfusion. To investigate the neuropharmacological mechanisms of CBD, the animals were injected with CB₁ (AM251, 1 mg/kg), CB₂ (AM630, 1 mg/kg), 5-HT_1A (WAY-100635, 10 mg/kg) or PPAR-γ (GW9662, 3 mg/kg) receptor antagonists 0.5 h prior to each injection of CBD. The animals were evaluated using a multi-task testing battery that included the open field (OF), elevated zero maze (EZM), Y-maze (YM), and forced swim test (FST). CBD prevented anxiety-like behavior, memory impairments, and despair-like behaviors induced by BCCAO in mice. The anxiolytic-like effects of CBD in BCCAO mice were attenuated by CB₁ , CB₂ , 5-HT_1A , and PPAR-γ receptor antagonists. In the YM, both CBD and the CB₁ receptor antagonist AM251 increased the exploration of the novel arm in ischemic animals, indicating beneficial effects of these treatments in the spatial memory performance. Together, these findings indicate the involvement of CB₁ , CB₂ , 5-HT_1A, and PPAR-γ receptors in the functional recovery induced by CBD in BCCAO mice.