BLOCKADE OF THE CENTRAL 5-HT AUTORECEPTOR BY BETA-ADRENOCEPTOR ANTAGONISTS

The release of [3H]5-HT from superfused rat frontal cortex slices was elicited by continuous exposure to either Krebs or Krebs buffer containing excess K+ (25 mmol/l). The basal release of [3H]5-HT was augmented by 1 .mu.mol/l of the (+)-isomers of the .beta.-adrenoceptor antagonists alprenolol, oxprenolol and pindolol. Neither the (-)-isomers of these drugs nor (.+-.)-atenolol (10 .mu.ml/l), (.+-.)-ICI 118551 (0.3 .mu.mol/l) or (.+-.)-cyanopindolol (0.008-0.1 .mu.mol/l) increased basal release. At these concentrations, however, the stimulation-evoked overflow was enhanced by (-)-alprenolol, (-)-oxprenolol and (.+-.)-cyanopindolol by not but (-)-pindolol. The inhibitory effects of 5-HT at the 5-HT autoreceptor were antagonised by (.+-.)-cyanopindolol (pA2 8.32), (-)-alprenolol (6.82), (-)-pindolol (6.66) and (-)-oxprenolol (6.28) whereas the .beta.1- and .beta.2-selective antagonists, atenolol and ICI 118551 respectively, were inactive. These studies utilising .beta.-adrenoceptor antagonists have defined a new class of 5-HT autoreceptor antagonists and, in addition, have identified (.+-.)-cyanopindolol as the most potent blocker of this receptor thus far identified.