Yohimbine as a serotonergic agent: Evidence from receptor binding and drug discrimination

Stimulus control was established in rats trained to discriminate either 8- hydroxy-2-(di-n-propylamino)tetralin (DPAT) (0.2 mg/kg) or yohimbine (3 mg/kg) from saline. Tests of generalization were then conducted with a group of drugs thought to act via the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor and a group of drugs thought to act as antagonists at alpha₂ adrenoceptors. In addition, each drug was characterized in terms of its affinity for 5- HT(1A) and alpha₂ adrenoceptors by means of radioligand binding techniques. It was observed that the stimulus effects of DPAT generalized fully to those of the alpha₂-adrenoceptor antagonists, yohimbine, rauwolscine and L- 657,743, but not to idazoxan or atipamezole. The dissociation constants (K(d), nM) of the alpha₂-adrenoceptor antagonists at the 5-HT(1A) receptor were 74, 52, 80, 199 and 13,000, respectively. Thus, the discrimination data are explicable in terms of a direct action of yohimbine and some other alpha₂ adrenoceptor antagonists upon 5-HT(1A) receptors. In yohimbine- trained rats, full generalization to DPAT, flesinoxan and tandospirone was observed. In light of the negligible affinity of flesinoxan and tandospirone for the alpha₂ adrenoceptor (9000 and 8800 nM, respectively), and high affinity for the 5-HT(1A) receptor (0.3 and 43 nM, respectively), a mechanism mediated by the latter site is suggested. We would emphasize two implications of the present study. First, the present data suggest that rats trained with yohimbine as a discriminative stimulus generalize to drugs with minimal affinity for the alpha₂ adrenoceptor but with high affinity for 5-HT(1A) receptors. Second, studies in which yohimbine is used to assess the function of the alpha₂ adrenoceptor should also consider the possible involvement of 5-HT(1A) receptors.