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-adrenergic receptor antagonist rauwolscine may function as an agonist at the serotonin1A (5-HT1A) receptor expressed in human brain. To directly test that hypothesis, we transfected the human 5-HT1A receptor cDNA into CHO cells and examined the ability of rauwolscine and its isomer, yohimbine, to inhibit ligand binding of [H-3]-(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin ([H-3]8-OH-DPAT) and the activity of adenylyl cyclase in membranes derived from a single transformant that stably expresses 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 yohimbine), yielding shallow displacement curves consistent with agonist activity (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 nontransfected) cells. For rauwolscine, the IC50 was 1.5 +/- 0.2 muM, and for yohimbine 4.6 +/- 1.0 muM, with activity ratios of 0.70 and 0.59, respectively, when compared to the full agonist serotonin. These studies demonstrated that rauwolscine and yohimbine are partial agonists for the human 5-HT1A receptor.