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.
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.
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DOI：
10.1021/acsptsci.3c00137
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发表时间：
2023-09
影响因子：
6
通讯作者：
Richa Tyagi;Tanishka S. Saraf;Clinton E. Canal
中科院分区：
文献类型：
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作者：
Richa Tyagi;Tanishka S. Saraf;Clinton E. Canal
能神经递质的迷幻裸盖菇素在治疗神经精神障碍中显示出功效，尽管其治疗作用的潜在机制仍不清楚。我们发现，类似的迷幻色胺，N，N-二丙基色胺（DPT），完全防止听源性癫痫发作（AGS）在Fmr 1敲除小鼠模型的脆性X综合征在10毫克/公斤的剂量，但不是在较低的剂量（3或5.6毫克/公斤）。尽管体外试验表明DPT是一种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-HT 2A/2C、5-HT 1B或5-HT 1A受体的选择性抑制剂预处理并不能阻断DPT的抗癫痫作用;泛5-HT受体拮抗剂也无效。由于5-HT 1A受体激活阻断了Fmr 1基因敲除小鼠的AGS，我们进行了剂量反应实验，以评估DPT在体内与5-HT 1A受体的结合。DPT仅在剂量大于10 mg/kg时引起5-HT 1A依赖性效应，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σ 1受体拮抗剂NE-100，不影响DPT的抗癫痫作用，表明DPT的σ 1受体的参与不是一个重要的机制。另外，我们观察到高剂量的DPT和NE-100本身引起惊厥，这在性质上不同于AGS。总之，DPT剂量依赖性地阻断了Fmr 1基因敲除小鼠的AGS，但5-羟色胺和sigma 1受体拮抗剂都不能阻止这种作用。因此，DPT可能具有独立于其多巴胺能致幻剂特性的神经治疗作用。然而，DPT在高剂量下也会引起癫痫发作，表明DPT具有复杂的剂量依赖性体内多药理学作用。
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.