Hallucinogens Activate a Specific Population of Neurons in the Cortex

Summary

Serotonin hallucinogens such as LSD and DOI primarily act through the 5-HT2A receptor, but their effects on brain function at the cellular and network levels remain incompletely understood. In adult rats treated with LSD, DOI, or saline, the somatosensory and medial prefrontal cortices were collected and dissociated into single cells. Using fluorescence-activated flow cytometry to separate neurons from glia and activated from non-activated neurons, qPCR analysis revealed an enrichment of immediate early genes (including c-fos, fosb, arc, krox-20/egr-2) in a small population of activated cortical neurons. Differences in gene abundance (htr2a, slc17a7, gad67) between activated and non-activated cells indicate which specific cell types are directly activated. Further research is needed to determine how this transcriptional program contributes to long-term psychological changes.

Study at a glance

Abstract

Serotonin hallucinogens produce a range of cognitive, sensory, and emotional effects in man. Recently, a resurgence of clinical interest in these compounds has developed because they can produce pronounced and long‐lasting psychological changes. While the structural backbones and receptor pharmacology of hallucinogens vary, their primary effects arise from agonism of the 5‐HT 2A receptor. However, our understanding of how these drugs produce changes in brain function at a neuronal level and network level is incomplete. The studies reported here aim to uncover properties of cells which are activated by the hallucinogens lysergic acid diethylamide (LSD) and 2,5‐dimethoxy‐4‐iodoamphetamine (DOI). Adult rats are treated with LSD, DOI, or saline, and the somatosensory and medial prefrontal cortices are collected and dissociated into single cell suspensions. We then use fluorescence‐activated flow cytometry (FACS) to separate neurons from glia and activated neurons from non‐activated neurons. Isolated populations of neurons are examined for changes in mRNA levels using qPCR analysis. We find an enrichment of a broad collection of immediate early genes (including c‐fos , fosb , arc , krox‐20/egr‐2 ) in a small population of activated neurons in the cortex. Additionally, the abundance of a variety of other genes ( htr2a , slc17a7 , gad67 ) in activated versus non‐activated cells provides evidence for which specific cell types are being directly activated by hallucinogens. Further research is required to determine the role the transcriptional program in activated cells plays in the development of long‐term effects initiated by hallucinogens.