The effect of chronic ritanserin and clorgyline administration on 5-HT2 receptor linked inositol phospholipid hydrolysis.
We have previously shown that chronic administration of the 5-hydroxytryptamine (5-HT) receptor antagonist, ritanserin (10 mg/kg/day) or the monoamine oxidase type A inhibitor (MAOI), clorgyline (2 mg/kg/day), results in a reduction in 5-HT2 receptor number in rat cerebral cortex. This study investigates the effects of acute and chronic ritanserin administration, on 5-HT2 receptor linked inositol phospholipid hydrolysis in rat cortical slices and compares it with the effect of a chronic clorgyline regimen. [3H]Myo-inositol (50 microCi) was used to label inositol phospholipids. Their subsequent hydrolysis in the presence or absence of 5-HT was determined by the accumulation of [3H]myoinositol monophosphate ([3H]InsP). Addition of 5 nM ritanserin to slices had no effect on basal or 5-HT stimulated [3H]InsP accumulation whereas 100 nM ritanserin blocked the stimulated response by 65%. Acutely, ritanserin (15 mg/kg i.p.) completely blocked 5-HT stimulated [3H]InsP accumulation. Chronic ritanserin or clorgyline treatment had no effect on basal levels of [3H]InsP accumulation compared to controls (mean value 3125 +/- 298 dpm/mg protein). Ritanserin increased 5-HT stimulated [3H]InsP accumulation at 1 microM, 100 microM and 1 mM 5-HT and this effect was significant at 100 microM 5-HT. Clorgyline had no significant or consistent effect on 5-HT stimulated [3H]InsP accumulation at 1 microM, 100 microM and 1 mM 5-HT. Thus the effects of both chronic clorgyline and ritanserin administration on 5-HT2 linked inositol phospholipid hydrolysis do not correlate with their effects on 5-HT2 receptor number (Bmax). The situation is further complicated since ritanserin significantly increases phosphatidylinositol (PtdIns), phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) labelling whereas clorgyline significantly increases PtdIns and PtdIns4P labelling. The implications of this are discussed.
Twist
E C
EC
Department of Neuroscience, Institute of Psychiatry, London, U.K.
Brammer
M J
MJ
Stephenson
J D
JD
Corn
T H
TH
Campbell
I C
IC
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003010:Clorgyline / Q000494:pharmacology*; D006868:Hydrolysis / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D016713:Ritanserin; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D010716:Phosphatidylinositols; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D016713:Ritanserin; D012701:Serotonin; D003010:Clorgyline