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

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, IF: 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, IF) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IF), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IF), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IF) and ketanserin (1.0 mg/kg, IF), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IF), 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, IF), 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, IF], 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, IF]. WAY-100635 (1.0 mg/kg, IF) in combination with ritanserin (3.0 mg/kg, IF), but not ondansetron (0.1 mg/kg, IF), GR 125487D (3.0 mg/kg, SC), or GR 127935 (30 mg/kg, IF), 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.