Regulation of Expression of Cannabinoid CB(2) and Serotonin 5HT(1A) Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons

Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB(2) and serotonin 5HT(1A) receptors included. These two receptors may interact to form heteromers (CB(2)–5HT(1A)-Hets) that are also a target of CBD. Aims: We aimed to assess whether the expression and function of CB(2)–5HT(1A)-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen-deprived neurons. Methods: We developed a quantitation of signal transduction events in a heterologous system and in glucose/oxygen-deprived neurons. The expression of receptors was assessed by immuno-cyto and -histochemistry and, also, by using the only existing technique to visualize CB(2)–5HT(1A)-Hets fixed cultured cells and tissue sections (in situ proximity ligation PLA assay). Results: CBD and cannabigerol, which were used for comparative purposes, affected the structure of the heteromer, but in a qualitatively different way; CBD but not CBG increased the affinity of the CB(2) and 5HT(1A) receptor–receptor interaction. Both cannabinoids regulated the effects of CB(2) and 5HT(1A) receptor agonists. CBD was able to revert the upregulation of heteromers occurring when neurons were deprived of oxygen and glucose. CBD significantly reduced the increased expression of the CB(2)–5HT(1A)-Het in glucose/oxygen-deprived neurons. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of CB(2)–5HT(1A)-Hets. Conclusions: Benefits of CBD in the hypoxia of the neonate are mediated by acting on CB(2)–5HT(1A)-Hets and by reducing the aberrant expression of the receptor–receptor complex in hypoxic-ischemic conditions. These results reinforce the potential of CBD for the therapy of the hypoxia of the neonate.