STUDIES ON THE ROLE OF 5-HT1A AUTORECEPTORS AND ALPHA(1)-ADRENOCEPTORS IN THE INHIBITION OF 5-HT RELEASE .1. BMY7378 AND PRAZOSIN

The present study utilized in vivo microdialysis to investigate the importance of 5-HT1A autoreceptors and alpha(1)-adrenoceptors in the decreased 5-HT release obtained following administration of the mixed 5-HT1A autoreceptor partial agonist/alpha(1)-adrenoceptor antagonist BMY7378, the selective 5-HT1A receptor agonist 8-OH-DPAT and the alpha(1)-adrenoceptor antagonist prazosin. BMY7378 (0.25 mg/kg, s.c.), 8-OH-DPAT (0.025 mg/kg, s.c.) and prazosin (0.1-1.0 mg/kg, s.c.) all suppressed ventral hippocampal 5-HT efflux. The BMY7378- and 8-OH-DPAT-induced inhibition of 5-HT release were reversed by a 40 min pre-treatment with either(+/-)pindolol (8 mg/kg, s.c.) or WAY-100635 (0.3 mg/kg, s.c.), to block 5-HT1A autoreceptors. Neither of these antagonists altered the prazosin-induced (0.3 mg/kg, s.c.) 5-HT decrease. The results: (i) confirm that both an alpha(1)-adrenoceptor antagonist (prazosin) and 5-HT1A autoreceptor stimulants (BMY7378 and 8-OH-DPAT) may reduce cerebral 5-HT release; (ii) support that the BMY7378-induced decrease in 5-HT release results from 5-HT1A autoreceptor agonism, rather than alpha(1)-adrenoceptor blockade; and (iii) argue against ''physiological'' antagonism (i.e, via blockade of beta-adrenoceptors, 5-HT1B receptors or some other mechanism) as an explanation for the reversal by pindolol of 5-HT1A autoreceptor agonist-induced suppression of 5-HT release. These data support the usefulness of pindolol, as well as the more specific compound WAY-100635, to block 5-HT1A autoreceptors.