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

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.