Importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity: An in vivo microdialysis study in the freely-moving guinea-pig

The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SE 219085, SE 220272; SE 224289 and SE 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SE 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SE 224289 and SE 219085 were inverse agonists, SE 220272 was an antagonist and SE 216641 was a partial agonist. SE 220272, SE 216641 and SE 224289 had no effect on extracellular 5-HT following systemic administration, however, SE 219085 produced a significant increase. The SE 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [H-3]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HT1A receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist. (C) 1997 Elsevier Science Ltd.