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 im portance of 5-HT1A autoreceptors and alpha(1)-adrenoceptors in the dec reased 5-HT release obtained following administration of the mixed 5-H T1A autoreceptor partial agonist/alpha(1)-adrenoceptor antagonist BMY7 378, 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-DPA T (0.025 mg/kg, s.c.) and prazosin (0.1-1.0 mg/kg, s.c.) all suppresse d 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 wit h 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 t he 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 cereb ral 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'' a ntagonism (i.e, via blockade of beta-adrenoceptors, 5-HT1B receptors o r some other mechanism) as an explanation for the reversal by pindolol of 5-HT1A autoreceptor agonist-induced suppression of 5-HT release. T hese data support the usefulness of pindolol, as well as the more spec ific compound WAY-100635, to block 5-HT1A autoreceptors.