Hexahydrocannabinol (HHC) activates cannabinoid receptor 1 (CB1R) in ways only broadly comparable to Δ9-tetrahydrocannabinol (Δ9-THC), with each HHC epimer showing unique signaling properties. HHC's greater chemical stability than Δ9-THC makes it a potential candidate for modern medicine. The study examined the pharmacodynamics of HHC epimers and their activation of CB1R-mediated signaling pathways, comparing them to those activated by Δ9-THC.
Coactivating muscarinic acetylcholine receptors and eliciting depolarization-induced suppression of excitation (DSE) in autaptic hippocampal neurons produces a roughly 40% inhibition of excitatory transmission lasting about 10 minutes. This inhibition, termed muscarinic cannabinoid suppression of excitation (MCSE), requires CB1 and muscarinic M3/M5 receptors and is absent in CB1 receptor knockout neurons. Once established, it is reversed by a CB1 antagonist but not a muscarinic antagonist, indicating persistent CB1 receptor activation. MCSE can be mimicked by coapplying muscarinic and cannabinoid agonists and depends on calcium release from internal stores. This represents a novel coincidence detection between cannabinoid and muscarinic signaling systems, potentially modulating hippocampal signaling with implications for learning, memory, epilepsy, and addiction.