5-HT1A RECEPTORS AND THE TAIL-FLICK RESPONSE .6. INTRINSIC ALPHA(1A)-ADRENOCEPTOR ANTAGONIST PROPERTIES CAN MASK THE ACTIONS OF 5-HT1A RECEPTOR AGONISTS IN THE SPONTANEOUS TAIL-FLICK PARADIGM

In view of the involvement of central alpha(1)-adrenoceptors in the ex pression of 5-HT1A receptor-mediated spontaneous tail-flicks (STFs) in the rat, this study examined whether the putative alpha(1)-adrenocept or antagonist (alpha(1)-antagonist) properties of certain 5-HT1A recep tor agonists, (+)-flesinoxan and LY 165,163, might modify their behavi or in the STF paradigm. Whereas the 5-HT1A receptor agonists 8-OH-DPAT and WY 48,723 dose-dependently elicited STFs, (+)-flesinoxan was only weakly active and LY 165,163 was ineffective. Further, (+)-flesinoxan and LY 165,163 antagonized the induction of STFs by 8-OH-DPAT and WY 48,723. Nevertheless, (+)-flesinoxan and LY 165,163 mimicked 8-OH-DPAT and WY 48,723 in eliciting a pronounced rise in plasma corticosterone and a marked hypothermia: these actions were blocked by the 5-HT1A re ceptor antagonist, (-)-alprenolol, but they were not affected by the a lpha(1)-antagonist prazosin. Reflecting its antagonist actions at cui- adrenoceptors, prazosin evoked a pronounced ptosis, an action mimicked by the preferential alpha(1A)-antagonists WB 4101, methylurapidil and benoxathian, whereas chlorethylclonidine, which irreversibly inactiva tes alpha(1B)- but not alpha(1A)-adrenoceptors, was inactive. Although 8-OH-DPAT and WY 48,723 failed to modify palpebral aperture, (+)-fles inoxan and LY 165,163 provoked a ptosis, suggesting that they possess alpha(1A)-antagonist properties. The alpha(1)-agonists cirazoline and ST 587 did not elicit STFs alone and failed to modify the induction of STFs by 8-OH-DPAT and WY 48,723. By contrast, they greatly facilitate d the ability of both (+)-flesinoxan and LY 165,163 to induce STFs. ST Fs elicited by (+)-flesinoxan and LY 165,163 in the presence of cirazo line or ST 587 were blocked not only by prazosin but also by (-)-alpre nolol, BMY 7378 and S 15535, all of which are antagonists of postsynap tic 5-HT1A receptors. The facilitatory actions of cirazoline and ST 58 7 were selective in that they did not permit the induction of STFs by agonists at other 5-HT receptor subtypes (5-HT1B, 5-HT1C, 5-HT2 or 5-H T3). In conclusion, in the STF paradigm, the high-efficacy agonist act ions of (+)-flesinoxan and LY 165,163 at 5-HT1A receptors are ''masked '' by their ''intrinsic'' alpha(1A)-antagonist properties, the neutral ization of which by alpha(1)-agonists reveals the activation of 5-HT1A receptors.