Male Sprague-Dawley rats were trained to discriminate the putative 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) from saline in a 2-lever operant drug discrimination paradigm. The 8-OH-DPAT cue was found to be highly selective; neither the 5-HT receptor agonists, quipazine, LSD, MK 212 and RU 24969, the 5-HT releasing agent, p-chloroamphetamine, nor the alpha 2-adrenoceptor agonist, clonidine, were able to substitute for 8-OH-DPAT in tests of generalization. In contrast, both buspirone and TVX Q 7821, which like 8-OH-DPAT have high affinity and selectivity for the 5-HT1A recognition site, generalized to the 8-OH-DPAT cue in a dose-dependent manner. The discriminative stimulus properties of 8-OH-DPAT were not antagonized by the 5-HT2 receptor antagonist, ketanserin, or the selective beta 1- and beta 2-adrenoceptor antagonists, betaxolol and ICI 118.551, indicating that neither 5-HT2 receptors, nor beta-adrenoceptors play a significant role in the behaviour. However, the 8-OH-DPAT cue was antagonized stereoselectively by pindolol and alprenolol, which have relatively high affinity and stereoselectivity for 5-HT1, but not 5-HT2, recognition sites. Similarly, the capacity of TVX Q 7821 to generalize to the 8-OH-DPAT cue could be blocked by pindolol. In view of the fact that 8-OH-DPAT has negligible affinity for the 5-HT1B site, the above results are consistent with its discriminative stimulus properties being mediated by the putative 5-HT1A receptor. Moreover, agonist activity at central 5-HT1A receptors may be an important mechanism contributing to the anxiolytic properties of buspirone and TVX Q 7821.
8-Hydroxy-2-(di-n-propylamino)tetralin Adrenergic alpha-Agonists