AGONIST OCCUPATION OF SEROTONIN(1A) RECEPTORS IN THE RAT HIPPOCAMPUS PREVENTS THEIR INACTIVATION BY PERTUSSIS TOXIN

The present study was undertaken to investigate the nature of the effe ct of pertussis toxin on the responsiveness of two potentially distinc t subgroups of postsynaptic serotonin(1A) (5-HT1A) receptors of rat hi ppocampus CA3 pyramidal neurons: those located at the level of the cel l body, which can be activated by microiontophoretically-applied 5-HT1 A receptor agonists, and those located on dendrites, which can be acti vated by endogenous serotonin released by the stimulation of the ascen ding serotoninergic pathway. The former receptors (denoted as extrasyn aptic) have been previously demonstrated to be sensitive to pertussis toxin, whereas the latter (denoted as intrasynaptic) have been shown t o be pertussis toxin-insensitive. Rats treated with the 5-HT1A recepto r agonists flesinoxan or BMY 42568 were used to determine whether toni c activation of extrasynaptic 5-HT1A receptors would prevent their ina ctivation by pertussis toxin. A pretreatment with p-chlorophenylalanin e was used to determine whether a serotonin depletion would render the intrasynaptic 5-HT1A receptors sensitive to pertussis toxin. The resp onsiveness of CA3 pyramidal neurons to the suppressant effects of micr oiontophoretically applied serotonin, 8-hydroxy-2-(di-n-propylamin)-te tralin, baclofen and GABA or to endogenously-released serotonin, elici ted by the stimulation of the ascending serotoninergic pathway, was st udied one to 10 days after the intrahippocampal injection of pertussis toxin. When compared to control saline-treated rats, the treatments w ith flesinoxan (5 mg/kg/day, s.c.) and BMY 42568 (5 mg/kg/day, s.c.) d elivered for 14 days by osmotic minipumps, starting three days prior t o the injection of pertussis toxin, significantly attenuated the effec t of pertussis toxin on the responsiveness of CA3 pyramidal neurons to microiontophoretic applications of serotonin and 8-hydroxy-2-(di-n-pr opylamino)-tetralin, as well as baclofen, an agonist of GABA(B) recept ors, which share the same G proteins with 5-HT1A receptors. The two-da y pretreatment with p-chlorophenylalanine (350 mg/kg/day, i.p.) did no t render the intrasynaptic 5-HT1A receptors sensitive to pertussis tox in, as indicated by the unchanged efficacy of the stimulation of the a scending serotonin pathway in the suppressing the firing activity of C A3 dorsal hippocampus pyramidal neurons. Our results suggest that the sustained activation of extrasynaptic 5-HT1A receptors prevents the pe rtussis toxin-induced ADP ribosylation of G protein alpha subunit, and thereby protects an amount of G proteins sufficient to maintain the f unction, not only of 5-HT1A, but also of GABA(B) receptors. The observ ation that the intrasynaptic 5-HT1A receptors remained pertussis toxin -insensitive, despite lowering of endogenous serotonin content, furthe r suggests that these 5-HT1A receptors may be functionally distinct ex trasynaptic 5-HT1A receptors.