5-HYDROXYTRYPTAMINE (5-HT)1A RECEPTORS AND THE TAIL-FLICK RESPONSE .1. 8-HYDROXY-2-(DI-N-PROPYLAMINO) TETRALIN HBR-INDUCED SPONTANEOUS TAIL-FLICKS IN THE RAT AS AN INVIVO MODEL OF 5-HT1A RECEPTOR-MEDIATED ACTIVITY

This study pharmacologically characterizes a novel behavioral response as a potential in vivo model of serotonin (5-HT)1A receptor-mediated activity. In rats restrained in horizontal cylinders, the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin HBr (8-OH-DPAT), dose-dependently (0.04-10.0 mg/kg s.c.) elicited spontaneous tail-flicks (STFs). This action was mimicked by other ligands possessing high affinity and high efficacy at 5-HT1A sites: RU 24969 [(5-methoxy-3-(1,2,3,6-tetra-hydropyridin-4-yl)-1H-indole], lisuride, (+)-lysergic acid diethylamide and 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate. The response could not be elicited by CGS 12066B [7-trifluormethyl-4-(4-methyl-/-piperazonyl)-pyrrolol-[1-2-a]quinoxaline dimaleate], mCPP 1-(3-chlorophenyl)-piperazine-2-HCl, TFMPPm-trifluromethylphenylpiperazine HCl, MK 212 [6-chloro-2-(l-piperazinyl)pyrazine], quipazine and DOI (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl, which act in vivo as agonists at 5-HT1B, 5-HT1C and/or 5-HT2 receptors, or by the 5-HT3 agonist, 2-methyl-5-HT. p-chloroamphetamine, which releases endogenous 5-HT, also evoked STFs; in contrast, d-amphetamine, a preferential releaser of catecholamines, was inactive, as were agonists and antagonists at alpha-1, alpha-2, beta-1, beta-2, dopamine D1 and D2 sites. 8-OH-DPAT-elicited STFs were blocked by the 5-HT1/2 antagonist, methiothepin, but not by the 5-HT1c/5-HT2 antagonists, mianserin, ritanserin and ICI 169,369 [2-(2-dimethylaminoetheylthio)-3-phenylquinoline] nor by the 5-HT3 antagonists, GR 38032F {1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-l-yl)methyl]-4H-carbazol-4-one HCl}, ICS 205,930 [(3-alpha-tropanyl)-1H-indol-3-carboxylic acid ester] and MDL 72222 [(1-alpha-H,3-alpha,5-alpha-H)-tripan-3-yl-3,5-dichlorobenzoate]. beta-Blockers with high 5-HT1A affinity i.e., (-)-alprenolol, (+/-)-isamoltane and, stereoselectively, (-)- but not (+)-pindolol, blocked the action of 8-OH-DPAT. Spiperone and spiroxatrine, D2 antagonists with high 5-HT1A affinity, also inhibited 8-OH-DPAT-induced STFs. Selective beta-blockers and D2 antagonists with low 5-HT1A affinity were inactive. 5-HT1A partial agonists, the pyrimidinylpiperazines, buspirone, gepirone and ipsapirone, the halogenated phenylpiperazine, LY 165,163 [1-(2-(4-aminophenyl) ethyl-4-(3-trifluoromethylphenyl)-piperazine], and the benzodioxane, MDL 72832 [8-(4-(1,4-benzodioxan-2-yl-methylamino)-butyl-8-azaspiro-(4,5)-decane-7,9-dione] did not elicit STFs and antagonized the effect of 8-OH-DPAT. The heterobicyclic arylpiperazine selective 5-HT1A ligand, (+/-)-flesinoxan, also failed to evoke STFs and attenuated the action of 8-OH-DPAT. The novel, putative 5-HT1A antagonists, BMY 7378 {(8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol-[4]-decane-7,9-dione 2HCl} and NAN-190 {1-(2-methoxyphenyl)-4-[4-(2-phtalimmido)butyl]-8-azaspiro-(4,5)-decane-7,9-dione], abolished the action of 8-OH-DPAT and p-chloroamphetamine. It is concluded that a high efficacy agonist action at 5-HT1A receptors is sufficient for the induction of STFs in the rat. This response offers a novel, robust and quantitative test for the in vivo characterization of drugs acting at 5-HT1A receptors.