Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice
M. de la Fuente Revenga, Urjita H. Shah, Nima Nassehi, Alaina M. Jaster, P. Hemanth, S. Sierra, M. Dukat, J. González-Maeso
ACS Chemical Neuroscience January 5, 2021 DOI: 10.1021/acschemneuro.0c00291 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice and in vitro assays |
| Intervention | Quipazine |
| Measures | [3H]ketanserin binding displacement, Ca2+ mobilization, inositol monophosphate (IP1) accumulation, immediate early gene (IEG) expression, head-twitch response (HTR) |
| Key findings | Quipazine bound to and activated the 5-HT2AR in vitro and in vivo, induced an immediate early gene expression pattern in mouse somatosensory cortex consistent with classic psychedelics, and produced a lasting head-twitch response that was blocked by the 5-HT2AR antagonist M100907 and absent in 5-HT2AR knockout mice. The authors argue these results add to evidence that quipazine's profile matches that of classic psychedelic 5-HT2AR agonists. |
Abstract
Known classic psychedelic serotonin 2A receptor (5-HT2AR) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT2AR can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HT2AR as measured by [3H]ketanserin binding displacement, Ca2+ mobilization, and accumulation of the canonical Gq/11 signaling pathway mediator inositol monophosphate (IP1) in vitro and in vivo. Additionally, quipazine induced via 5-HT2AR an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HT2AR antagonist M100907 and absent in 5-HT2AR knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HT3R activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine’s profile matches that of classic psychedelic 5-HT2AR agonists at cellular signaling and behavioral pharmacology levels.