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-hydroxytryptamine1A (5-HT1A) receptor and a group of drugs thought to act as antagonists at alpha 2 adrenoceptors. In addition, each drug was characterized in terms of its affinity for 5-HT1A and alpha 2 adrenoceptors by means of radioligand binding techniques. It was observed that the stimulus effects of DPAT generalized fully to those of the alpha 2-adrenoceptor antagonists, yohimbine, rauwolscine and L-657,743, but not to idazoxan or atipamezole. The dissociation constants (Kd, nM) of the alpha 2-adrenoceptor antagonists at the 5-HT1A 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 alpha 2 adrenoceptor antagonists upon 5-HT1A 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 alpha 2 adrenoceptor (9000 and 8800 nM, respectively), and high affinity for the 5-HT1A 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 alpha 2 adrenoceptor but with high affinity for 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Winter
J C
JC
Department of Pharmacology and Therapeutics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo.
Rabin
R A
RA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D054833:Isoindoles; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C055267:tandospirone; D015016:Yohimbine; D012701:Serotonin; C056895:flesinoxan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin