This experimental study investigated the effects of N,N-dipropyltryptamine (DPT), a psychedelic tryptamine, on audiogenic seizures in a mouse model of fragile X syndrome (genetic cause of autism). DPT was found to prevent seizures at a 10 mg/kg dose completely but not at lower doses (3 or 5.6 mg/kg). Despite being a serotonin receptor agonist, the antiepileptic effects of DPT were not mediated through specific serotonin receptor subtypes (5-HT2A, 5-HT1B, or 5-HT1A), nor through sigma1 receptors.
Abstract of DPT Prevents Seizures in a Mouse Model of Fragile X Syndrome
“The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or 5.6 mg/kg). Despite showing in vitro that DPT is a serotonin 5-HT2A, 5-HT1B, and 5-HT1A receptor agonist (with that rank order of functional potency, determined with TRUPATH Gα/βγ biosensors), pretreatment with selective inhibitors of 5-HT2A/2C, 5-HT1B, or 5-HT1A receptors did not block DPT’s antiepileptic effects; a pan-serotonin receptor antagonist was also ineffective. Because 5-HT1A receptor activation blocks AGS in Fmr1 knockout mice, we performed a dose–response experiment to evaluate DPT’s engagement of 5-HT1A receptors in vivo. DPT elicited 5-HT1A-dependent effects only at doses greater than 10 mg/kg, further supporting that DPT’s antiepileptic effects were not 5-HT1A-mediated. We also observed that the selective sigma1 receptor antagonist, NE-100, did not impact DPT’s antiepileptic effects, suggesting DPT engagement of sigma1 receptors was not a crucial mechanism. Separately, we observed that DPT and NE-100 at high doses caused convulsions on their own that were qualitatively distinct from AGS. In conclusion, DPT dose-dependently blocked AGS in Fmr1 knockout mice, but neither serotonin nor sigma1 receptor antagonists prevented this action. Thus, DPT might have neurotherapeutic effects independent of its serotonergic psychedelic properties. However, DPT also caused seizures at high doses, showing that DPT has complex dose-dependent in vivo polypharmacology.”
Authors: Richa Tyagi, Tanishka S. Saraf & Clinton E. Canal
Summary of The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors
Studies are investigating psychedelics, including psilocybin and related psychedelic tryptamines, for various psychiatric conditions, including major depressive disorder (MDD), substance-use disorders, autism spectrum disorder (ASD), and fragile X syndrome (FXS). However, the specific pharmacodynamic properties that contribute to the therapeutic efficacies of psychedelics are not well understood. There has been a resurgence of interest in 5-HT and its receptors as novel antiepileptics, owing to the recently proven antiepileptic effects of fenfluramine in Dravet syndrome and Lennox-Gastaut syndrome. However, the functions of distinct 5-HT2R subtypes in modulating distinct types of epilepsy remain unsolved.
In preclinical models, activation of 5-HT1ARs is antiepileptic. For example, WAY-100635, a selective 5-HT1AR antagonist, inhibits the anti-AGS effect in Fmr1 KO mice of the selective 5-HT1A agonist, NLX-112.
The authors tested the hypothesis that the serotonergic psychedelic N,N-dipropyltryptamine (DPT) would prevent AGS in juvenile Fmr1 KO mice and that its antiepileptic effects would be effective via a serotonergic or sigma1R mechanism. DPT is not restricted as a Schedule 1 controlled substance.
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https://doi.org/10.1021/acsptsci.3c00137
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Cite this paper (APA)
Tyagi, R., Saraf, T. S., & Canal, C. E. (2023). The Psychedelic N, N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors. ACS Pharmacology & Translational Science.
Study details
Participants
75
Rodents