Effects of a Serotonergic Psychedelic on the Lipid Bilayer.

The serotonergic psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) alters the physical properties of artificial lipid bilayers in ways that may contribute to its biological effects, such as enhancing neuronal plasticity. Using solid-state NMR, atomic force microscopy, and fluorescence techniques, DOI was found to induce disorder in lipid acyl chains, shrink ordered domains, reduce the force needed to form nanopores, and promote vesicle fusion to lipid bilayers. These receptor-independent effects on membranes are more than two orders of magnitude more potent than those of serotonin. The findings suggest that direct membrane actions of psychedelics, not just serotonin 2A receptor activation, could play a role in processes requiring membrane remodeling.

Study at a glance

Abstract

Serotonergic psychedelics, known for their hallucinogenic effects, have attracted interest due to their ability to enhance neuronal plasticity and potential therapeutic benefits. Although psychedelic-enhanced neuroplasticity is believed to require activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs), serotonin itself is less effective in promoting such plasticity. Also, the psychoplastogenic effects of these molecules correlate with their lipophilicity, leading to suggestions that they act by influencing the intracellular receptors. However, their lipophilicity also implies that a significant quantity of lipids is accumulated in the lipid bilayer, potentially altering the physical properties of the membrane. Here, we probe whether the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) can affect the properties of artificial lipid bilayers and if that can potentially affect processes such as membrane fusion. Solid-state NMR spectroscopy shows that the DOI strongly induces disorder in the lipid acyl chains. Atomic force microscopy shows that it can shrink the ordered domains in a biphasic lipid bilayer and can reduce the force needed to form nanopores in the membrane. Fluorescence correlation spectroscopy shows that DOI can promote vesicle association, and total internal fluorescence microscopy shows that it enhances vesicle fusion to a supported lipid bilayer. While serotonin has also recently been shown to cause similar effects, DOI is more than two orders of magnitude more potent in evoking these. Our results suggest that the receptor-independent effects of serotonergic psychedelics on lipid membranes may contribute to their biological actions, especially those that require significant membrane remodeling, such as neuronal plasticity.