4-(3-Indolyl-2-ethyl)
piperidine (
LM 5008), 2-(1-piperazinyl)
quinoline (
quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting
serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by
quipazine, which showed an IC50 of 3.8 X 10(-6) M.
LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and
quipazine were less potent than d-
fenfluramine in releasing 14C-5-HT from brain synaptosomes, while
LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on
5-HT uptake showed that
LM 5008 was the most potent compound in inhibiting
5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of
LM 5008 27-times higher than the ED50 for inhibiting
5-HT uptake in vivo, it is suggested that even marked inhibition of
5-HT uptake at central synapses is not sufficient per se to trigger
serotonin-dependent
anorexia in the rat. Increased release and/or direct stimulation of post-
synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause
anorexia by interacting with brain
serotonin.