Scholarlink

<p>Psilocybin is a serotonergic psychedelic drug with emerging therapeutic applications, yet its actions under glutamatergic dysfunction, and relevance to schizophrenia and associated psychiatric disorders, remain unclear. We examined the acute and long-lasting effects of psilocybin (1 mg/kg, intraperitoneal) on behavioral and neural outcomes in the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia. The mGlu5 KO mice displayed psilocybin-induced hyperlocomotion, whereas wild-type (WT) mice did not. Additionally, male mGlu5 KO mice showed an amplified psilocybin-induced head-twitch response (HTR) compared with WT males, consistent with sex-dependent enhancement of 5-HT<sub>2A</sub> receptor-mediated signaling. Acute psilocybin increased c-Fos expression in the claustrum of WT but not KO mice, suggesting intact mGlu5 signaling is required for psilocybin-evoked claustral recruitment. Psilocybin did not alter anxiety-like behavior in the light–dark box and increased immobility time&#xa0;in the Porsolt test. Strikingly, psilocybin produced a sustained normalization in prepulse inhibition (a measure of sensorimotor gating) in female KO mice, evident nine days after treatment. Together, these findings indicate that disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. These results refine understanding of glutamatergic–serotonergic interactions and motivate further work evaluating psilocybin across schizophrenia-relevant endophenotypes.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月18日

查看全文
  • James J. Gattuso,
  • Ahmed Kamal,
  • Jennyfer M. Payet,
  • Kato Havaux,
  • Jenna Hendey,
  • Bilgenur Bezcioglu,
  • Zoe J. Phelan,
  • Maddy Orchard,
  • Divyesh Bhanot,
  • Matthew W. Hale,
  • Anthony J. Hannan,
  • Thibault Renoir

摘要

Psilocybin is a serotonergic psychedelic drug with emerging therapeutic applications, yet its actions under glutamatergic dysfunction, and relevance to schizophrenia and associated psychiatric disorders, remain unclear. We examined the acute and long-lasting effects of psilocybin (1 mg/kg, intraperitoneal) on behavioral and neural outcomes in the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia. The mGlu5 KO mice displayed psilocybin-induced hyperlocomotion, whereas wild-type (WT) mice did not. Additionally, male mGlu5 KO mice showed an amplified psilocybin-induced head-twitch response (HTR) compared with WT males, consistent with sex-dependent enhancement of 5-HT2A receptor-mediated signaling. Acute psilocybin increased c-Fos expression in the claustrum of WT but not KO mice, suggesting intact mGlu5 signaling is required for psilocybin-evoked claustral recruitment. Psilocybin did not alter anxiety-like behavior in the light–dark box and increased immobility time in the Porsolt test. Strikingly, psilocybin produced a sustained normalization in prepulse inhibition (a measure of sensorimotor gating) in female KO mice, evident nine days after treatment. Together, these findings indicate that disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. These results refine understanding of glutamatergic–serotonergic interactions and motivate further work evaluating psilocybin across schizophrenia-relevant endophenotypes.