THE ROLE OF 5-HT1A AUTORECEPTORS AND ALPHA(1)-ADRENOCEPTORS IN THE INHIBITION OF 5-HT RELEASE .2. NAN-190 AND SDZ-216-525

Novel 5-HT1A receptor antagonists, WAY 100135 and WAY 100635, were use d to test the involvement of 5-HT1A receptors in the decrease of hippo campal extracellular 5-HT induced by the 5-HT1A/alpha 1 ligands, NAN-1 90 and SDZ 216-525. Using microdialysis in anaesthetised rats, it was found that WAY 100135 (3 mg/kg s.c.) and WAY 100635 (0.3 mg/kg s.c.) a ntagonised the decrease of 5-HT induced by the 5-HT1A receptor agonist 8-OH-DPAT (0.025 mg/kg s.c.) but did not alter 5-HT when administered alone;Both NAN-190 (0.03 and 0.3 mg/kg s.c.) and SDZ 216-525 (1 mg/kg s.c.) decreased 5-HT. The effect of 0.03 mg/kg s.c. NAN-190 was antag onised by WAY 100135 (3 mg/kg s.c.) and WAY 100635 (0.3 mg/kg s.c.). T he effect of SDZ 216-525 (1 mg/kg s.c.) was also blocked by WAY 100635 (0.3 mg/kg s.c.). However, the 5-HT response to a high-dose of NAN-19 0 (0.3 mg/kg s.c.) was not antagonised by WAY 100635 (0.3 or 3 mg/kg s .c.). Our experiments using WAY 100635 and WAY 100135 provide clear ev idence that NAN-190 and SDZ 216-525 act as agonists at the 5-HT1A auto receptor, supporting our earlier studies using the non-selective 5-HT1 A antagonist, pindolol. However, our data reveal that, at least in the case of NAN-190, non-5-HT1A receptor mechanisms mediate the decrease of 5-HT induced by higher doses. A lack of specifity of NAN-190 (and p ossibly SDZ 216-525) at high doses may explain the failure of previous studies to detect a 5-HT1A receptor agonist action. Copyright (C) 199 6 Elsevier Science Ltd.