An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats.
The effect of fluoxetine on feeding in p-chlorophenylalanine (PCPA) pretreated rats and the nature of its interaction with 5-HT2C receptors have been investigated. Animals that received 3 days PCPA (150 mg/kg i.p.) pretreatment and vehicle on the test day consumed a similar amount as control, saline pretreated animals under the test paradigm used in this study. Fluoxetine (20 and 30 mg/kg p.o.) significantly reduced food intake in PCPA and control pretreated animals to a similar extent, despite an approximately 90% reduction in the levels of brain 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the PCPA-pretreated animals. Thus, hypophagia is unlikely to be caused by inhibition of 5-HT reuptake. In the pig choroid plexus in vitro, fluoxetine and norfluoxetine inhibited specific [3H] mesulergine binding with pKI's (+/- S.E.M.) of 6.45 +/- 0.09 (n = 4) and 6.05 +/- 0.05 (n = 3), and slope factors (+/- S.E.M.) of 1.06 +/- 0.14 and 0.99 +/- 0.13, respectively. In slices of piglet choroid plexus fluoxetine (1, 10 and 33 microM) caused a rightward shift in the dose-response curve produced by 5-HT with no effect on the maximal response, and a mean pKB of 5.94 +/- 0.09. Norfluoxetine (10 microM) also produced a rightward shift in the 5-HT dose-response curve with no effect on the maximal response, and a pKB of 6.20. Thus, both compounds acted as surmountable antagonists with no agonist efficacy at 5-HT2C receptors present in choroid plexus. The hypophagic effect of fluoxetine (20 mg/kg p.o.) was also unaffected by the non-specific 5-HT2C receptor antagonist metergoline (2 and 5 mg/kg i.p.). These findings suggest that the hypophagic effect of fluoxetine is not likely to be dependent upon intact brain 5-hydroxytryptaminergic presynaptic function, nor is it mediated by an agonist action at the 5-HT2C receptor, but by an additional, unknown mechanism.
Lightowler
S
S
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Wood
M
M
Brown
T
T
Glen
A
A
Blackburn
T
T
Tulloch
I
I
Kennett
G
G
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008711:Metergoline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013552:Swine
D001067:Appetite Depressants; D010134:Fenclonine; D005473:Fluoxetine; D006897:Hydroxyindoleacetic Acid; D008711:Metergoline; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors