Receptor mechanisms underlying the CNS effects of cannabinoids: CB₁ receptor and beyond

Cannabis legalization continues to progress in many US states and other countries. Δ⁹-tetrahydrocannabinol (Δ⁹-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 Δ⁹-THC or other cannabinoids (WIN55212-2) with a focus on their receptor mechanisms. In experimental animals, Δ⁹-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 CB₁Rs underlies the majority of Δ⁹-THC or WIN55121-2's pharmacological and behavioral effects. Unexpectedly, glutamatergic CB₁Rs preferentially underlie cannabis action relative to GABAergic CB₁Rs. Functional roles for CB₁Rs expressed on astrocytes and mitochondria have also been uncovered. In addition, Δ⁹-THC or WIN55212-2 is an agonist at CB₂R, 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 Δ⁹-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.