RESUMEN
1-(2-Methoxyphenyl)-4-[(phthalimido)butyl] piperazine (NAN-190) and 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5] decane-7,9-dione (buspirone) are 5-HT1A receptor partial agonists which decrease 5-hydroxytryptamine (5-HT) release in vivo. In order to assess whether these ligands decrease 5-HT release by stimulating 5-HT1A receptors we examined the ability of the selective 5-HT1A receptor antagonist N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride (WAY-100135) to block their inhibitory effects on 5-HT. NAN-190 (0.1 mg/kg s.c.) and buspirone (1.0 mg/kg s.c.) significantly decreased extracellular levels of 5-HT in hippocampal dialysates. WAY-100135 (10.0 mg/kg s.c.) attenuated the effect of buspirone but had no significant effect on the NAN-190-induced decreased in 5-HT release. These data demonstrate that buspirone is an agonist at the somatodendritic 5-HT1A receptor but that the inhibitory effects of NAN-190 on 5-HT release may be mediated via a mechanism other than, or in addition to, 5-HT1A receptor agonism.
Asunto(s)
Buspirona/farmacología , Hipocampo/metabolismo , Piperazinas/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Serotonina/metabolismo , Animales , Interacciones Farmacológicas , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Hipocampo/efectos de los fármacos , Inyecciones Subcutáneas , Masculino , Ratas , Ratas Sprague-Dawley , Técnicas EstereotáxicasRESUMEN
SDZ 216,525 has been proposed to be a silent 5-HT1A receptor antagonist. The present study examined the potential intrinsic agonist action of SDZ 216,525 using two in vivo models of somatodendritic 5-HT1A autoreceptor function: 5-HT release using microdialysis and feeding behaviour of satiated animals. SDZ 216,525 (1 mg/kg s.c.) and the alpha 1-adrenoceptor antagonist prazosin (1 mg/kg s.c.) significantly decreased hippocampal 5-HT release. In addition, SDZ 216,525 (3 and 10 mg/kg s.c.) and prazosin (3 and 10 mg/kg s.c.) significantly increased food intake in satiated rats. The selective 5-HT1A receptor antagonist (RS)-WAY100135 (10 mg/kg s.c.) which has been demonstrated to block the effects of 8-OH-DPAT on 5-HT release and food intake had no significant effect on the response induced by SDZ 216,525. In contrast, the non-selective 5-HT1A receptor antagonist (-)-pindolol (8 mg/kg s.c.) attenuated both SDZ 216,525 responses. The decrease in hippocampal 5-HT release and increase in food intake induced by SDZ 216,525 suggest that the compound may be a 5-HT1A receptor partial agonist. However, the failure of the 5-HT1A receptor antagonist (RS)-WAY100135 to block the SDZ 216,525 responses suggests that SDZ 216,525 decreases 5-HT release and increases food intake by a mechanism other than 5-HT1A receptor agonism. The high affinity of SDZ 216,525 for the alpha 1-adrenoceptor, and the ability of prazosin to decrease 5-HT release and increase food intake, suggest that the effects of SDZ 216,525 may be mediated via an alpha 1-adrenoceptor antagonist action.
Asunto(s)
Dendritas/metabolismo , Indoles/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Tiazoles/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Dendritas/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Microdiálisis , Pindolol/farmacología , Piperazinas/farmacología , Prazosina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacosRESUMEN
The neurochemical profile of the selective 5-HT1A receptor antagonist WAY100135 [N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride] and its enantiomers at the somatodendritic 5-HT1A receptor was determined by studying the effects of these compounds on 5-HT (5-hydroxytryptamine, serotonin) release in the rat hippocampus using in vivo microdialysis. (+/-)-WAY100135, (+)-WAY100135 and (-)-WAY100135 (all at 10 mg/kg s.c.) had no significant effect on extracellular levels of 5-HT in the hippocampus demonstrating that these compounds are devoid of 5-HT1A receptor agonist properties. In contrast, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1 mg/kg s.c.) and the partial agonists BMY 7378 (1.0 mg/kg s.c.) and buspirone (5 mg/kg s.c.) significantly decreased hippocampal 5-HT. Pretreatment with (+/-)-WAY100135 (at 10 mg/kg s.c.) and (+)-WAY100135 (at 1.0-10 mg/kg s.c.) completely blocked the 8-OH-DPAT-induced decrease in 5-HT release demonstrating that these compounds are antagonists at the somatodendritic 5-HT1A autoreceptor. (-)-WAY100135 at a dose of 10 mg/kg s.c. had no significant effect on the 8-OH-DPAT-induced inhibition of 5-HT release. (+/-)-WAY100135 had no significant effect on extracellular levels of dopamine in the rat hippocampus but significantly increased extracellular levels of noradrenaline. The mechanism underlying the increase in noradrenaline is unknown at present.(ABSTRACT TRUNCATED AT 250 WORDS)