5-HT1A receptors and the tail-flick response. VI. 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 expression of 5-HT1A receptor-mediated spontaneous tail-flicks (STFs) in the rat, this study examined whether the putative alpha 1-adrenoceptor antagonist (alpha 1-antagonist) properties of certain 5-HT1A receptor agonists, (+)-flesinoxan and LY 165,163, might modify their behavior 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 receptor antagonist, (-)-alprenolol, but they were not affected by the alpha 1-antagonist prazosin. Reflecting its antagonist actions at alpha 1-adrenoceptors, prazosin evoked a pronounced ptosis, an action mimicked by the preferential alpha 1A-antagonists WB 4101, methylurapidil and benoxathian, whereas chlorethylclonidine, which irreversibly inactivates alpha 1B- but not alpha 1A-adrenoceptors, was inactive. Although 8-OH-DPAT and WY 48,723 failed to modify palpebral aperture, (+)-flesinoxan 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 facilitated the ability of both (+)-flesinoxan and LY 165,163 to induce STFs. STFs elicited by (+)-flesinoxan and LY 165,163 in the presence of cirazoline or ST 587 were blocked not only by prazosin but also by (-)-alprenolol, BMY 7378 and S 15535, all of which are antagonists of postsynaptic 5-HT1A receptors. The facilitatory actions of cirazoline and ST 587 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-HT3). In conclusion, in the STF paradigm, the high-efficacy agonist actions of (+)-flesinoxan and LY 165,163 at 5-HT1A receptors are "masked" by their "intrinsic" alpha 1A-antagonist properties, the neutralization of which by alpha 1-agonists reveals the activation of 5-HT1A receptors.
Millan
M J
MJ
Department of Psychopharmacology, Institut de Recherches Servier, Paris, France.
Rivet
J M
JM
Gobert
A
A
Canton
H
H
Veiga
S
S
Bervoets
K
K
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004347:Drug Interactions; D005143:Eyelids / Q000187:drug effects / Q000502:physiology; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D008954:Models, Biological; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013623:Tail / Q000502:physiology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C081273:WY 48723; C056895:flesinoxan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C044643:LY 165163; D003345:Corticosterone