Down-regulation of [3H]5-hydroxytryptamine binding sites in chick embryo brain by monoamine oxidase inhibitors or fenfluramine and potentiation by d,l-5-hydroxytryptophan.
Three monoamine oxidase (MAO) inhibitors--pargyline, clorgyline and deprenyl--as well as the serotonin (5-HT, 5-hydroxytryptamine) releasing agent fenfluramine were administered to developing chick embryos and the effects on [3H]5-HT binding parameters and endogenous 5-HT levels were assessed. Multiple, but not acute, pretreatments with any of the three MAO inhibitors significantly increased 5-HT levels (p less than 0.01) and decreased receptor number (Bmax) to a maximum of 20% (p less than 0.01) without affecting the affinity (KD). When d,l-5-hydroxytryptophan (d,l-5-HTP) was similarly administered there were large increases in 5-HT levels (p less than 0.01), but no significant effects on either Bmax or KD. However, if d,l-5-HTP was co-administered with any of the MAO inhibitors there was a significant (p less than 0.01) enhancement of the MAO inhibitor-induced down-regulation to a maximum of about 40%. Multiple pretreatments with fenfluramine resulted in dose-related decreases in 5-HT levels (p less than 0.01) and Bmax (p less than 0.01) without affecting KD. The largest decrease in [3H]5-HT binding sites inducible by fenfluramine treatment alone was also about 40%. When given in combination with d,l-5-HTP, there was a potentiation of the down-regulation capabilities of fenfluramine at several different dosage levels; however, maximal down-regulation was also limited to 40%. Evidence was presented suggesting that these effects were not due to endogenous 5-HT or drugs remaining in the tissue preparation. The overall evidence implies that merely increasing endogenous 5-HT levels, as by precursor administration, does not necessarily induce down-regulation unless the 5-HT is also made available as functional 5-HT.
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000196:embryology*; D002642:Chick Embryo; D003010:Clorgyline / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology*; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*
D008996:Monoamine Oxidase Inhibitors; D005277:Fenfluramine; D012642:Selegiline; D012701:Serotonin; D010293:Pargyline; D006916:5-Hydroxytryptophan; D003010:Clorgyline