Receptor mechanisms underlying the CNS effects of cannabinoids: CB receptor and beyond.

Cannabis legalization continues to progress in many US states and other countries. Δ-tetrahydrocannabinol (Δ-THC) is the major psychoactive constituent in cannabis underlying both its abuse potential and the majority of therapeutic applications. However, the neural mechanisms underlying cannabis action are not fully understood. In this chapter, we first review recent progress in cannabinoid receptor research, and then examine the acute CNS effects of Δ-THC or other cannabinoids (WIN55212-2) with a focus on their receptor mechanisms. In experimental animals, Δ-THC or WIN55212-2 produces classical pharmacological effects (analgesia, catalepsy, hypothermia, hypolocomotion), biphasic changes in affect (reward vs. aversion, anxiety vs. anxiety relief), and cognitive deficits (spatial learning and memory, short-term memory). Accumulating evidence indicates that activation of CBRs underlies the majority of Δ-THC or WIN55121-2's pharmacological and behavioral effects. Unexpectedly, glutamatergic CBRs preferentially underlie cannabis action relative to GABAergic CBRs. Functional roles for CBRs expressed on astrocytes and mitochondria have also been uncovered. In addition, Δ-THC or WIN55212-2 is an agonist at CBR, GPR55 and PPARγ receptors and recent studies implicate these receptors in a number of their CNS effects. Other receptors (such as serotonin, opioid, and adenosine receptors) also modulate Δ-THC's actions and their contributions are detailed. This chapter describes the neural mechanisms underlying cannabis action, which may lead to new discoveries in cannabis-based medication development for the treatment of cannabis use disorder and other human diseases.