The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test

Psychopharmacology (Berl). 1998 Feb;135(4):383-91. doi: 10.1007/s002130050526.


We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (> 30), dose dependently reduced shock-induced USV. The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of the mixed 5-HT2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/kg, SC), or GR 127935 (30 mg/kg, IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT1A and 5-HT2A receptors produces a decrease of USV, we postulate that only 5-HT2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology
  • Serotonin Uptake Inhibitors / pharmacology*
  • Ultrasonics
  • Vocalization, Animal / drug effects*


  • Anti-Anxiety Agents
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors