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

Abstract

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-HT 2A , 5-HT 1B , and 5-HT 1A receptor agonist (with that rank order of functional potency, determined with TRUPATH Gα/βγ biosensors), pretreatment with selective inhibitors of 5-HT 2A/2C , 5-HT 1B , or 5-HT 1A receptors did not block DPT's antiepileptic effects; a pan-serotonin receptor antagonist was also ineffective. Because 5-HT 1A receptor activation blocks AGS in Fmr1 knockout mice, we performed a dose−response experiment to evaluate DPT's engagement of 5-HT 1A receptors in vivo. DPT elicited 5-HT 1A -dependent effects only at doses greater than 10 mg/kg, further supporting that DPT's antiepileptic effects were not 5-HT 1A -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 dosedependent in vivo polypharmacology.

Synthesis and Structure–Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist

“…The three main classes of serotonergic psychedelics, tryptamines, lysergamides, and phenylalkylamines, share pharmacology as 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor agonists. It is thought that activation of central 5-HT 2A receptors, which generates psychedelic experiences, is responsible for the psychotherapeutic effects of psychedelics, though this is not yet conclusive. − Most serotonergic psychedelics have other pharmacological targets in addition to 5-HT 2 receptors. For example, psilocin binds several other 5-HT G protein-coupled receptors (GPCRs), and lysergic acid diethylamide (LSD), the quintessential psychedelic, binds several 5-HT and other GPCRs. − …”