Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

Neuron. 2007 Sep 6;55(5):712-25. doi: 10.1016/j.neuron.2007.07.041.

Abstract

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / metabolism
  • Depressive Disorder / physiopathology
  • Disease Models, Animal
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Male
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Phosphorylation / drug effects
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Serotonin, 5-HT4 / metabolism
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / metabolism*
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT4 Receptor Agonists*
  • Serotonin Receptor Agonists / pharmacology*
  • Serotonin Receptor Agonists / therapeutic use
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Time Factors

Substances

  • Aniline Compounds
  • Antidepressive Agents
  • Cyclic AMP Response Element-Binding Protein
  • Piperidines
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT4 Receptor Agonists
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Receptor, Serotonin, 5-HT1A
  • Receptors, Serotonin, 5-HT4
  • RS 67333
  • Serotonin