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

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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 ( IF 4.9 ) Pub Date : 2023-09-18 , DOI: 10.1021/acsptsci.3c00137
Richa Tyagi ₁ , Tanishka S Saraf ₁ , Clinton E Canal ₁

Affiliation

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 dose-dependent in vivo polypharmacology.

中文翻译：

迷幻的 N,N-二丙基色胺通过一种独立于血清素和 Sigma1 受体的机制预防脆性 X 综合征小鼠模型的癫痫发作

血清素能迷幻裸盖菇素在治疗神经精神疾病方面显示出功效，但其治疗作用的机制仍不清楚。我们发现，在脆性 X 综合征的Fmr1敲除小鼠模型中，类似的迷幻色胺N , N-二丙基色胺 (DPT) 在 10 mg/kg 剂量下可以完全预防听源性癫痫发作 (AGS)，但在较低剂量（3 或 5.6毫克/千克）。尽管体外显示 DPT 是一种血清素 5-HT _2A 、 5-HT _1B和 5-HT _1A受体激动剂（按照功能效力的等级顺序，用 TRUPATH Gα/βγ 生物传感器测定），但用 5 种选择性抑制剂进行预处理-HT _2A/2C 、5-HT _1B或 5-HT _1A受体不阻断 DPT 的抗癫痫作用；泛血清素受体拮抗剂也无效。由于 5-HT _1A受体激活会阻断Fmr1敲除小鼠中的 AGS，因此我们进行了剂量反应实验来评估 DPT 在体内与 5-HT _1A受体的结合。 DPT 仅在剂量大于 10 mg/kg 时才引发 5-HT _1A依赖性作用，进一步支持 DPT 的抗癫痫作用不是 5-HT _1A介导的。我们还观察到选择性 sigma1 受体拮抗剂 NE-100 不会影响 DPT 的抗癫痫作用，这表明 sigma1 受体的 DPT 参与并不是一个关键机制。另外，我们观察到高剂量的 DPT 和 NE-100 会自行引起惊厥，这在性质上与 AGS 不同。总之，DPT 剂量依赖性地阻断Fmr1敲除小鼠中的 AGS，但血清素和 sigma1 受体拮抗剂都不能阻止这种作用。因此，DPT 可能具有独立于其血清素能迷幻特性的神经治疗作用。然而，DPT 在高剂量时也会引起癫痫发作，表明 DPT 具有复杂的剂量依赖性体内多药理作用。

更新日期：2023-09-18

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