Lysergic Acid Diethylamide (LSD) Modulates Circadian Activity Behavior And The Expression Level of Circadian Genes in Drosophila melanogaster in Both Sexes

Summary

Lysergic acid diethylamide (LSD), a mixed serotonin receptor agonist, alters circadian activity in Drosophila melanogaster in a dose-dependent manner, with a more robust effect in females. Five concentrations (0.01, 0.1, 1.0, 3.0, and 10.0 mM) were administered for seven days in a light/dark environment, and activity was monitored using the Drosophila Activity Monitor. LSD disrupted endogenous circadian rhythms in free run (dark/dark) conditions at doses of 1.0 and 3.0 mM in both sexes. Changes in RNA levels of circadian and P450 genes in fly heads were measured. The findings suggest LSD affects circadian activity potentially through modulating expression of circadian genes downstream of serotonin receptor activation.

Study at a glance

Abstract

Circadian rhythms modulate biochemical and molecular pathways in living systems. In humans an endogenous clock mechanism is synchronized by a daily light‐dark cycle: sun up and sun down. These external cues from the environment regulate the core‐clock through auto‐regulating circadian genes’ expression levels. These oscillating gene products modulate physiological, biochemical, and molecular pathways that maintain homeostasis of cells and the overall homeostasis of a living organism. Drosophila and other model organisms are utilized to study the input pathways that modulate the core clock and its regulation of circadian rhythms. Our laboratory has previously used serotonin agonists to study behaviors in the fly, but the role of serotonin and its receptors in circadian behaviors have not been studied extensively. Therefore to study the impact of serotonin receptor linked pathways on circadian gene expression, we investigated the effects of the pharmacological agent lysergic acid diethylamide (LSD), a mixed serotonin receptor agonist, on circadian activity in the fly. In humans, studies have shown that LSD affects the sleep/wake circadian rhythms, but the mechanism is not known. Although, LSD has not been used to study circadian activity rhythms in the fly, previous work in the laboratory demonstrated that serotonin and its receptors play a role in modulating circadian related activity in the fly, We therefore hypothesize that LSD will alter clock gene expression levels and disrupt circadian activity in Drosophila. The Drosophila Activity Monitor (DAM) was used to record circadian activity in entrain (light/dark) and free run (dark/dark) environments. The Capillary Feeding (CAFE) assay was simultaneously used to measure food/drug consumption. Five concentrations (0, 0.01, 0.1, 1.0, 3.0, and 10.0 mM) of LSD were administered to the flies for seven days in a light/dark environment, during which time the flies were monitored for activity levels. Our data show that LSD affects circadian activity in the fly in a dose‐dependent manner in both males and females, with a more robust effect in females. Changes were measured in the RNA levels of circadian and P450 genes in the fly heads between LSD‐treated and control flies. In free run experiments three doses of LSD (0, 1.0 and 3.0mM) were tested, and these data show that LSD also disrupts the endogenous circadian rhythm in a dose dependent manner in both males and females. These behavioral experiments and molecular studies suggest that LSD affects circadian activity, potentially through modulating expression of circadian genes downstream of serotonin receptor activation.