In vivo characterization of the putative 5-HT1A receptor antagonist SDZ 216,525 using two models of somatodendritic 5-HT1A receptor function.
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.
Routledge
C
C
Department of Neuropharmacology, Wyeth Research (U.K.) Ltd., Maidenhead, Berkshire.
Hartley
J
J
Gurling
J
J
Ashworth-Preece
M
M
Brown
G
G
Dourish
C T
CT
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010869:Pindolol / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D007211:Indoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013844:Thiazoles; C081293:WAY 100135; C080378:SDZ 216-525; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010869:Pindolol; D011224:Prazosin