Psilocybin and ketamine affect novel neuropeptides gene expression in the rat hypothalamus

Pałasz, Artur and Pukowiec, Marta and Bogus, Katarzyna and Suszka-Świtek, Aleksandra and Filipczyk, Łukasz and Mordecka-Chamera, Kinga and Worthington, John J and Sygidus, Maria and Wojtas, Adam and Bysiek, Agnieszka and Gołembiowska, Krystyna (2025) Psilocybin and ketamine affect novel neuropeptides gene expression in the rat hypothalamus. Journal of Psychopharmacology. ISSN 0269-8811

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Abstract

OBJECTIVE: Psychedelics are able to trigger highly intense and profound alterations in self-consciousness, perception, affective, and cognitive processes. Indeed, recent studies show that ketamine and psilocybin could be used as fast-acting antidepressants. However, the molecular and neurochemical mechanisms of these psychedelics and their actions at the level of diverse brain structures remains so far unclear. Hypothalamic neuropeptides are involved in a wide spectrum of neuronal activities being responsible for the central control of all fundamental autonomic functions. METHODS: The purpose of this exploratory pilot study was to assess the gene expression of both classical and novel neuropeptides, including nesfatin-1, phoenixin (PNX), spexin (SPX), neuromedin U (NMU), neuropeptide S (NPS), and their known receptors in the hypothalamus of male Wistar-Han rats subjected to single injections of psilocybin (dose 2 or 10 mg/kg) and ketamine (dose10 mg/kg). Total mRNA was isolated from homogenized tissue and real-time PCR was used for estimation of related gene expression. RESULTS: It was found that a single administration of the higher dose of psilocybin increased the mRNA expression of most noncanonical neuropeptides examined in the study, with only the case of NMU there with a decrease in gene expression. Interestingly, psilocybin administration also increased mRNA expression of the serotonin receptors: 5-HT1A, 5-HT2A, and 5-HT2B, but not 5HT-2C. In contrast, the effect of ketamine on the expression of neuropeptides was much more limited compared to psilocybin, only increasing transcripts of NUCB2, GPR173, and POMC were demonstrated. CONCLUSIONS: These results suggest for the first time that selected psychedelics may enhance the signaling of 5-HT2A receptors or inhibit NMDA receptor activity, affecting neuropeptide signaling and serotonin transmission in the rat hypothalamus, which may contribute to a better understanding of psychedelic action in the brain.