Snapshot of 5-HT 2A receptor activation in the mouse brain via IP 1 detection.
bioRxiv : the preprint server for biology – October 12, 2024
Source: PubMed
Summary
Scientists have discovered a new way to track how psychedelic drugs like LSD affect specific brain receptors. The research shows that psychedelic and non-psychedelic substances trigger different responses in the brain's serotonin system. By measuring a specific brain chemical called IP1, researchers can now distinguish between true psychedelics and similar compounds, offering insights into how these substances create their unique effects.
Abstract
The distinct subjective effects that define psychedelics such as LSD, psilocybin or DOI as drug class are causally linked to activation of the serotonin 2A receptor (5-HT 2A R). However, some aspects of 5-HT 2A R pharmacology remain elusive, such as what molecular drivers differentiate psychedelic from non-psychedelic 5-HT 2A R agonists. We developed an ex vivo platform to obtain snapshots of drug-mediated 5-HT 2A R engagement of the canonical G q/11 pathway in native tissue. This non-radioactive methodology captures the pharmacokinetic and pharmacodynamic events leading up to changes in inositol monophosphate (IP 1 ) in the mouse brain. The specificity of this method was assessed by comparing IP 1 levels in homogenates from the frontal cortex in DOI-treated wild-type and 5-HT 2A R-KO animals compared to other brain regions, namely striatum and cerebellum. Furthermore, we encountered that head-twitch response (HTR) counts and IP 1 in the frontal cortex were correlated. We observed that IP 1 levels in frontal cortex homogenates from mice treated with LSD and lisuride vary in magnitude, consistent with LSD's 5-HT 2A R agonism and psychedelic nature, and lisuride's lack thereof. MDMA evoked an increase of IP 1 signal in the frontal cortex that were not matched by the serotonin precursor 5-HTP or the serotonin reuptake inhibitor fluoxetine. We attribute differences in the readout primarily to the indirect stimulation of 5-HT 2A R by MDMA via serotonin release from its presynaptic terminals. This methodology enables capturing a snapshot of IP 1 turnover in the mouse brain that can provide mechanistic insights in the study of psychedelics and other serotonergic agents pharmacodynamics.