Effects of mu-CPP and mesulergine on dietary choices in deprived rats: possible mechanisms of their action.
Although it has been well established that compounds that stimulate 5-HT(2C) and/or 5-HT(1B) receptors induce hypophagia by promoting satiety process, the relative role of these receptor subtypes in dietary choices remains to be fully determined. m-CPP is considered a useful probe of 5-HT(2C) receptor function in vivo and its administration reduces food intake and appetite in humans and rats. Conversely, the non-selective 5-HT(2C) receptor antagonist mesulergine elicits feeding in rats. Food intake and dietary choices were measured in a food-deprivation experimental protocol employing male Wistar rats. Animals were given access for a 4-h period to a pair of isocaloric diets. These two diets were enriched in protein or carbohydrate proportions, respectively, but fat content was held constant. The mixed 5-HT(2C/1B) receptor agonist, m-CPP, led to a dose-dependent hypophagia, due to substantial reduction in carbohydrate consumption while protein intake was spared (0.62, 1.25 and 2.50 mg/kg i.p., respectively). The non-selective 5-HT(2C) receptor antagonist and also D2 agonist, mesulergine, on its own produced a significant dose-dependent increase in both protein and carbohydrate diets (1.0 and 3.0 mg/kg i.p., respectively). Combined treatment with m-CPP, at its maximum effective dose, and mesulergine dose-dependently reversed m-CPP-induced hypophagia, during the 4-h test period. In order to clarify the effects of mesulergine on dietary choices since it is simultaneously a dopamine agonist besides its antiserotonergic properties, the D2 agonist apomorphine was also used. Apomorphine caused a dose-dependent increase in protein intake while carbohydrate and total food intake remained nearly unchanged (0.5 and 1.0 mg/kg i.p., respectively). It is concluded that the mesulergine-induced hyperphagic response on both diets is the expression of a dual mode of action, due to its 5-HT(2C) antagonist activity together with D2 agonist properties. The results further indicate that the activation of hypothalamic 5-HT(2C) receptors may be involved in both protein sparing and carbohydrate suppressing effects of 5-HT (m-CPP-like effect), whereas an important role in increase of protein consumption seems to have the dopaminergic system probably through D2 receptors (apomorphine-like and mesulergine-like effects, respectively).
Antonatos
Spyridon
S
Department of Experimental Pharmacology, Medical School, University of Athens, 75, M. Asias, str, Athens 11527, Goudi, Greece. sorfeas@otenet.gr
Galanopoulou
Panagiota
P
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects*; D004032:Diet / Q000379:methods; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004873:Ergolines / Q000494:pharmacology*; D005508:Food Deprivation / Q000502:physiology*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D018491:Dopamine Agonists; D004873:Ergolines; D010879:Piperazines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D001058:Apomorphine; C015068:1-(3-chlorophenyl)piperazine; C031649:mesulergine