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Chronic 5-HT7R activation drives depressive phenotypes and synaptic dysfunction.

Bartłomiej Pochwat1,2, Julia Masternak3, Bartosz Bobula4

  • 1Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093, Warsaw, Poland. pochwat@if-pan.krakow.pl.

Acta Pharmacologica Sinica
|February 3, 2026
PubMed
Summary
This summary is machine-generated.

Chronic activation of the 5-HT7 receptor (5-HT7R) in male mice induced depressive-like behaviors and altered synaptic plasticity. This research may inform strategies to mitigate side effects of selective serotonin reuptake inhibitors (SSRIs).

Keywords:
5-HT7RGαsdendritic spinesdepressive disordermatrix metalloproteinase 9 (MMP-9)serotonin receptor agonists

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Selective serotonin reuptake inhibitors (SSRIs) are common antidepressants, but chronic use causes side effects and residual depression symptoms.
  • These SSRI effects are linked to serotonin receptor signaling, yet molecular mechanisms remain unclear.
  • The 5-HT7 receptor (5-HT7R) is implicated in mood regulation and SSRI action.

Purpose of the Study:

  • To investigate the impact of chronic and acute 5-HT7R activation on behavior and molecular pathways in male mice.
  • To explore the role of 5-HT7R in mediating depressive-like behaviors and synaptic plasticity changes.
  • To understand potential mechanisms underlying SSRI-induced side effects.

Main Methods:

  • Administered a selective 5-HT7R agonist (AGH-194) acutely and chronically to male mice.
  • Conducted behavioral tests: novelty suppressed feeding (NSFT), female urine sniffing (FUST), and novel object location (NOLT).
  • Analyzed molecular changes (MMP-9, GluA1 expression), cellular morphology (dendritic spines), and electrophysiology (hippocampal excitability, plasticity).

Main Results:

  • Chronic AGH-194 induced depressive-like behaviors across multiple tests; acute AGH-194 induced it only in NSFT.
  • AGH-194 activated matrix metalloproteinase 9 (MMP-9) via 5-HT7R-Gαs signaling, with chronic treatment causing prolonged activation.
  • Chronic treatment reduced hippocampal GluA1 expression, altered dendritic spine morphology, and modulated hippocampal short-term plasticity.

Conclusions:

  • Chronic 5-HT7R activation can induce depressive-like behaviors in male mice, potentially via sustained MMP-9 activity and synaptic plasticity alterations.
  • Findings suggest 5-HT7R signaling contributes to SSRI-induced side effects.
  • Understanding these mechanisms could lead to improved antidepressant strategies targeting specific receptor pathways.