TOLERANCE DEVELOPMENT TO THE VAGAL-MEDIATED BRADYCARDIA PRODUCED BY 5-HT1A RECEPTOR AGONISTS

The purpose of this study was to characterize the bradycardic effects of 5-hydroxytryptamine (5-HT)(1A) receptor agonists in the chloralose- anesthetized spinal cat and to determine if tolerance develops to the bradycardia produced by these drugs. 5-HT1A receptor agonists studied included 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone , gepirone, flesinoxan and U-93385E (cis-(3aR)-(-)-2,3,3a,4,5,9b-hexah ydro-3-propyl-1 H-benz[e]indole-9-carboxamide). These compounds reduce d heart rate by 20 to 30% in the spinal cat and lowered arterial blood pressure. The hypotension resulted from a decrease in cardiac output. Atropine reversed and vagotomy prevented the bradycardia produced by a single dose of U-93385E. The decrease in heart rate produced by i.v. bolus doses of flesinoxan or U-93385 was reversed by administration o f the 5-HT1A receptor antagonists spiperone or WAY 100135. Administrat ion of a single dose of U-93385E (either 0.3, 1.0 or 3.0 mg/kg i.v.) r esulted in a 20 to 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 i n the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2- hr period failed to lower heart rate and prevented a bradycardic effec t of a single bolus dose of U-93385E or flesinoxan. In contrast, the a lpha-2 receptor agonist clonidine decreased heart rate in animals rece iving the U-93385E infusion. Finally, single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E and then saline for 3 days. These data indicate that 5-H T1A receptor agonists stimulate vagal nerve activity to decrease heart rate. Moreover, rapid and long-lived tolerance develops to the vagal bradycardic effects of 5-HT1A receptor agonists.