RESUMEN

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.

Asunto(s)

Antidepresivos , Corteza Cerebral , Alucinógenos , Plasticidad Neuronal , Receptor de Serotonina 5-HT2A , Agonistas del Receptor de Serotonina 5-HT2 , Alucinógenos/farmacología , Plasticidad Neuronal/efectos de los fármacos , Serotonina/farmacología , Transducción de Señal , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Animales , Ratones , Ratones Noqueados , Antidepresivos/farmacología