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

Abstract

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 hr before and 3, 24, and 48 hr after reperfusion. To investigate the neuropharmacological mechanisms of CBD, the animals were injected with CB 1 (AM251, 1 mg/kg), CB 2 (AM630, 1 mg/kg), 5-HT 1A (WAY-100635, 10 mg/kg), or PPAR-γ (GW9662, 3 mg/kg) receptor antagonists 0.5 hr prior to each injection of CBD. The animals were evaluated using a multi-task testing battery that included the open field, elevated zero maze, Y-maze (YM), and forced swim test. CBD prevented anxietylike behavior, memory impairments, and despair-like behaviors induced by BCCAO in mice. The anxiolytic-like effects of CBD in BCCAO mice were attenuated by CB 1 , CB 2 , 5-HT 1A , and PPAR-γ receptor antagonists. In the YM, both CBD and the CB 1 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 CB 1 , CB 2 , 5-HT 1A, and PPAR-γ receptors in the functional recovery induced by CBD in BCCAO mice.

Neuroprotective Effects of Cannabidiol but Not Δ9-Tetrahydrocannabinol in Rat Hippocampal Slices Exposed to Oxygen-Glucose Deprivation: Studies with Cannabis Extracts and Selected Cannabinoids

“…However, more recent findings indicate that CBD is not a full 5-HT1A receptor agonist as was originally proposed, but its mechanism of action seems to involve allosteric interactions with the receptor or interference with the intracellular pathways associated with this receptor [ 46 ]. In an in vivo model of transient global ischemia, Mori and colleagues investigated the ability of CBD to prevented anxiety-like behavior, memory impairments, and despair-like behaviors; in particular, the anxiolytic-like effects of CBD in global ischemia were attenuated by CB1, CB2, 5-HT1A, and PPARγ receptor agonists [ 47 ]. Different studies suggested that hippocampal neuronal-synaptic modulation by TRPV1 is a possible mechanism of action for CBD [ 48 , 49 , 50 ].…”

Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents

“…c&d: (PTX+5HT1AB+CBD or THCV): 5HT1A blocker (5HT1AB), 10 mg/kg/day, i.p., was given to mice for four weeks and three hours before administering CBD or THCV e&f: (PTX+CB2B+CBD or THCV): CB2 blocker (CB2B) 1 mg/kg/day, i.p., was given to mice for four weeks and three hours before administering CBD or THCV. The PTX, CBD, THCV, AM630, Rimonabant and WAY10065 dosages were determined using existing literature reports [16][17][18][19][20][21]. After the animals were euthanized using CO2 asphyxiation and dorsal root ganglions (L1-L5) were extracted, biochemical and molecular parameters were examined.…”

Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity

“…One limitation of the present study was that we did not investigate the pharmacological mechanism of action of CBD in rats with TGCI. We recently demonstrated the involvement of cannabinoid CB 1 , CB 2 , 5-HT 1A, and peroxisome proliferator-activated receptor-γ (PPAR-γ) receptors in functional recovery that is elicited by CBD in BCCAO mice [70]. Whether similar mechanisms are engaged in TGCI rats remains to be determined.…”