PARTIAL AGONIST PROPERTIES OF RAUWOLSCINE AND YOHIMBINE FOR THE INHIBITION OF ADENYLYL-CYCLASE BY RECOMBINANT HUMAN 5-HT(1A)-RECEPTORS

Previous studies by another group have suggested that the alpha2-adren ergic receptor antagonist rauwolscine may function as an agonist at th e serotonin1A (5-HT1A) receptor expressed in human brain. To directly test that hypothesis, we transfected the human 5-HT1A receptor cDNA in to CHO cells and examined the ability of rauwolscine and its isomer, y ohimbine, to inhibit ligand binding of [H-3]-(+/-)-8-hydroxy-2-(di-n-p ropylamino)tetralin ([H-3]8-OH-DPAT) and the activity of adenylyl cycl ase in membranes derived from a single transformant that stably expres ses almost-equal-to 225 fmol of 5-HT1A receptor/mg of membrane protein . Both ligands competitively antagonized the binding of [H-3]8-OH-DPAT (K(i) = 158 +/- 69 nM for rauwolscine and 690 +/- 223 nM for yohimbin e), yielding shallow displacement curves consistent with agonist activ ity (Hill values = 0.69 +/- 0.2 for rauwolscine and 0.63 +/- 0.06 for yohimbine). Both ligands also inhibited forskolin-stimulated adenylyl cyclase activity in membranes derived from transfected (but not nontra nsfected) cells. For rauwolscine, the IC50 was 1.5 +/- 0.2 muM, and fo r yohimbine 4.6 +/- 1.0 muM, with activity ratios of 0.70 and 0.59, re spectively, when compared to the full agonist serotonin. These studies demonstrated that rauwolscine and yohimbine are partial agonists for the human 5-HT1A receptor.