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+ ions (25 mmol/l). The basal release of [3H]5-HT was augmented by 1 mumol/l of the (+)-isomers of the beta-adrenoceptor antagonists alprenolol, oxprenolol and pindolol. Neither the (-)-isomers of these drugs nor (+/-)-atenolol (10 mumol/l), (+/-)-ICI 118551 (0.3 mumol/l) or (+/-)-cyanopindolol (0.008-0.1 mumol/l) increased basal release. At these concentrations, however, the stimulation-evoked overflow was enhanced by (-)-alprenolol, (-)-oxprenolol and (+/-)-cyanopindolol but not by (-)-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.