Rapid and long duration tolerance to the vagal bradycardic effects of 5-HT1A receptor agonists

Administration of a single dose of the 5-HT1A receptor high intrinsic agonist U-93385E (either 0.3, 1.0 or 3.0 mg/kg, i.v.) results in a 20-30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg, i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2 h period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha 2-receptor agonist clonidine decreased heart rate in Animals receiving the U-93385E infusion. Single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E (3 mg/kg, b.i.d.) and then saline for 3 days. Similarly, U-93385E failed to lower heart rate 12 days following a 14 day infusion of U-93385E (1 mg/kg per day). These data indicate that a rapid and long duration tolerance develops to the vagal bradycardia produced by 5-HT1A receptor agonists.