- Vargas, Maxemiliano V;
- Dunlap, Lee E;
- Dong, Chunyang;
- Carter, Samuel J;
- Tombari, Robert J;
- Jami, Shekib A;
- Cameron, Lindsay P;
- Patel, Seona D;
- Hennessey, Joseph J;
- Saeger, Hannah N;
- McCorvy, John D;
- Gray, John A;
- Tian, Lin;
- Olson, David E
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.