Δ⁹-tetrahydrocannabinol functions as a G protein-biased dopamine D₂ receptor agonist that drives sustained ERK...

Δ⁹-Tetrahydrocannabinol (THC), the principal psychoactive constituent of Cannabis sativa, exerts its central effects predominantly through the cannabinoid CB₁ receptor (CB₁R). However, molecular mechanisms underlying THC actions beyond canonical CB₁R signaling have been suggested but remain incompletely defined. Systematic screening of 14 structurally diverse cannabinoid compounds identified THC as a direct agonist at the dopamine D₂ receptor (D₂R). THC selectively activated ERK signaling through D2-like receptors, directly bound D₂R with submicromolar affinity, and functioned as a G protein-biased agonist that engages Gi/o-dependent signaling without recruiting arrestin pathways. Mechanistically, this biased signaling enabled D₂R to transactivate EGFR via a cascade involving Src, PI3K, and PKC. Activated EGFR, in turn, sustained phosphorylation of Src and PKCβII, establishing a positive feed-forward loop that prolongs ERK activation. These findings demonstrate that THC directly engages D₂R in parallel with the canonical CB₁R-mediated disinhibition of dopaminergic neurons, providing a comprehensive molecular framework that links cannabis exposure to aberrant dopaminergic signaling. By acting as a Gi/o-biased partial agonist at D₂R, THC is poised to both modulate canonical dopaminergic transmission and initiate a distinct EGFR-dependent signaling program. This dual mechanism offers a revised view of THC pharmacology and its potential contribution to neuropsychiatric effects associated with cannabis exposure.