Inverse agonists and serotonergic transmission: From recombinant, human serotonin (5-HT)(1B) receptors to G-protein coupling and function in corticolimbic structures in vivo

The concept of inverse agonism, whereby "antagonists" exert actions opposit e to those of agonists at constitutively active receptors, has been documen ted both at receptor modulated ion channels as well as at G-protein-coupled receptors (GPCR) in recombinant expression systems. However, it remains un clear whether physiologically or therapeutically relevant inverse agonists actions at GPCRs occur in the CNS in vivo. The present overview discusses o ur recent observations concerning 5-HT1B receptors, and focusses on the rel ationship between actions at heterologous Chinese hamster ovary (CHO) expre ssion systems compared with native CNS populations of receptors. To this en d, we have exploited several novel and selective ligands, notably the inver se agonist and neutral antagonist at 5-HT1B receptors, SB224,289 and S18127 , respectively. Like 5-HT itself, the agonist, GR46611, markedly increases the binding of [S-35]-GTP gamma S binding to h5-HT1B receptors expressed in CHO cells, while the "antagonist", GA127,935, modestly stimulates binding suggesting partial agonist properties. However, SB224,289 markedly suppress es binding at these sites. S18127, which does not alter [S-35]GTP gamma S b inding alone, abolishes the actions of both GX46611 and SB224,289. Neverthe less, in quantitative autoradiographical studies, S18127 and SB224,289 cann ot be distinguished as concerns modulation of [S-35]-GTP gamma S binding at substantia nigra and caudate nucleus-localized 5-HT1B receptors, inasmuch as they each block the action of the 5-HT1B agonist, CP93129, yet fail to m odify binding alone. Further, S18217 and SB224,289, as well as GR127,935, a ll abolish the inhibitory influence of GX46611 upon dialysis levels of 5-HT in the frontal cortex of freely moving rats without themselves modifying r elease. Moreover, they all block the hypothermic actions of GX46611 without themselves modifying cove temperature. Thus, differences in intrinsic ativ ity of S18127, SB224,289 and GR127,935 seen at cloned, h5-HT1B receptors ca nnot be detected in vivo. Most notably, no evidence for opposite actions of the inverse agonist, SB224,289, as compared to 5-HT1B agonists is apparent . These data suggest that in vitro observations of inverse agonist actions cannot necessarily be extrapolated to intact systems in vivo. (C) 1999 Amer ican College of Neuropsychopharmacology. Published by Elsevier Science Inc.