Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration

Lysergic acid diethylamide (LSD) transiently alters perception, behavior, and mood at very low doses, and its acute effects resemble symptoms of schizophrenia. Analyzing gene expression after LSD exposure is key to understanding how it changes behavior and to gaining insights into disorders like schizophrenia. Previous work identified a set of genes in the rat prefrontal cortex involved in synaptic plasticity that respond to LSD. This report details their expression using RNase protection analysis, showing a dynamic response: some genes increase and decrease rapidly, others change more gradually. Dose-response studies reveal two expression classes—maximally stimulated at lower doses or continuing to rise at higher doses. Most increases depend on the 5-HT(2A) receptor, but two genes involve neither 5-HT(1A) nor 5-HT(2A) receptors.

Study at a glance

Abstract

Lysergic acid diethylamide (LSD) is a psychoactive drug that transiently alters human perception, behavior, and mood at extremely low doses. Certain aspects of the behavior elicited by acute doses of LSD closely resemble symptoms of mental disorders such as schizophrenia. Characterizing gene expression profiles after LSD will be important for understanding how it alters behavior, and will lead to novel insights into disorders, such as schizophrenia, whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs. We previously identified a small collection of genes within the rat prefrontal cortex that respond to LSD. Many of the products of these genes are involved in the process of synaptic plasticity. In the current report, we present a detailed analysis of the expression of these genes within the brain using RNase protection analysis. We find that the gene response to LSD is quite dynamic. The expression of some genes increases rapidly and decreases rapidly, while other genes change more gradually. Dose-response studies show two classes of expression; gene expression maximally stimulated at lower doses, versus gene expression that continues to rise at the higher doses. The role of the 5-HT(1A) and 5-HT(2A) receptor in mediating the increases in gene expression was examined in a series of experiments using receptor specific antagonists. Most expression increases were due to activation of the 5-HT(2A) receptor, however expression of two genes had neither a 5-HT(1A) nor a 5-HT(2A) receptor component.