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 reu ptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1 B/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 par oxetine (3.0 mg/kg, IF) were not blocked by the selective 5-HT1A recep tor antagonist, WAY-100635 (3.0 mg/kg, IF), the 5-HT1B/1D receptor ant agonist, GR 127935 (30 mg/kg, IF), the nonselective 5-HT2A receptor an tagonists, 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-H T4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the s elective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IF), comp letely prevented the paroxetine-induced reduction of USV. Under simila r conditions, WAY-100635 blocked the anxiolytic-like effects of the se lective 5-HT1A receptor agonist, 8-OH-DPAT [(+/-)-8-hydroxy-2-(di-n-pr opylamino)tetralin, 1.0 mg/kg, IF], and ritanserin, ketanserin, and MD L 100,907 blocked the anxiolytic-like effects of the mixed 5-HT2A/2C r eceptor 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 ritanse rin (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 reduci ng 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 ef fects of SSRIs in this model of anxiety.