Site-selective serotonin agonists as discriminative stimuli.

Various direct- and indirect-acting serotonin (5-HT) agonists serve as training drugs in tests of stimulus control of behavior; such agents include: 5-hydroxytryptophan, 5-methoxy-N,N-dimethyltryptamine, and fenfluramine. However, with the recent discovery of multiple populations of central 5-HT binding sites, the concept of site-selective serotonergic agents needs to be addressed. Certain 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes such as DOM (4-methyl), DOB (4-bromo), and DOI (4-iodo) appear to be 5-HT2-selective agonists and serve as effective training drugs in rats. Stimulus generalization occurs among these agents regardless of which is used as the training drug, although stimulus generalization does not occur with 5-HT1A-selective agonists [e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)] or with 5-HT1B-selective agonists [e.g., 1-(3-trifluoromethylphenyl)piperazine (TFMPP)]. 8-OH DPAT and TFMPP also serve as training drugs; the 8-OH DPAT-stimulus generalizes to other 5-HT1A agonists, but not to 5-HT1B or 5-HT2 agonists, whereas the TFMPP-stimulus generalizes to other 5-HT1B agonists, but not to 5-HT1A or 5-HT2 agonists. Classical serotonin antagonists, most of which are rather selective for 5-HT2 sites, and 5-HT2-selective antagonists are able to block the stimulus effects of DOM, DOB, and DOI, but not those of 8-OH DPAT or TFMPP. The results of such studies reveal that, in rats, site-selective 5-HT agonists produce stimulus effects that are also selective; although generalization may occur with nonselective 5-HT agonists, animals trained to discriminate site-selective 5-HT agonists apparently do not recognize other 5-HT agonists that are selective for a different site. Animals trained to discriminate such agents from saline might be useful for the identification and/or investigation of novel site-selective agonists and antagonists (for example, the 8-OH DPAT-stimulus generalizes to members of a new class of anxiolytics that display high affinity for 5-HT1A binding sites), and might also aid in the overall understanding of central serotonergic mechanisms.