Effects of selective 5-HT1A receptor antagonists on regional serotonin synthesis in the rat brain: an autoradiographic study with alpha-[14C]methyl-L-tryptophan.
The effects of acute and chronic administration of WAY100635 and WAY100135, serotonin (5-HT)1A antagonists, on 5-HT synthesis rates, calculated from the trapping of alpha-[14C]methyl-L-tryptophan (alpha-MTrp), were evaluated in the rat brain using autoradiography. In the acute treatment studies, WAY100635 (1 mg/kg) induced a significant increase in 5-HT synthesis in the median raphe nucleus and some nerve terminal structures (range between 18 and 53%), while WAY100135 (10 mg/kg) produced a significant decrease of synthesis, in the range between 16 and 33%, in the raphe magnus nucleus and several projection areas. The action of WAY100635 given acutely was likely a result of antagonist actions at the 5-HT1A somato-dendritic autoreceptors. WAY100135 probably acted acutely as a partial agonist. In the chronic treatment studies, WAY100635 (1 mg/kg/day) and WAY100135 (10 mg/kg/day) were administered for 7 days as s.c. injections once a day. Chronic treatment with both compounds significantly reduced the rate of 5-HT synthesis in the nerve terminal structures and produced a significant increase in the raphe nuclei. These treatments did not have any effect on the plasma free or total tryptophan.
Tohyama
Y
Y
Cone Neurosurgical Research Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Quebec, Montreal, Canada.
Yamane
F
F
Merid
M F
MF
Diksic
M
M
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000096:biosynthesis*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C081293:WAY 100135; C020774:alpha-methyltryptophan; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D014364:Tryptophan