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Doi:10.1016/j.pnpbp.2005.08.018

Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 Effects of m-CPP and mesulergine on dietary choices in deprived rats: Spyridon Antonatos *, Panagiota Galanopoulou Department of Experimental Pharmacology, Medical School, University of Athens, 75, M. Asias, str, Athens 11527, Goudi, Greece Although it has been well established that compounds that stimulate 5-HT2C and/or 5-HT1B 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 usefulprobe of 5-HT2C receptor function in vivo and its administration reduces food intake and appetite in humans and rats. Conversely, the non-selective 5-HT2C 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-HT2C/1Breceptor agonist, m-CPP, led to a dose-dependent hypophagia, due to substantial reduction in carbohydrate consumption while protein intakewas spared (0.62, 1.25 and 2.50 mg/kg i.p., respectively). The non-selective 5-HT2C 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 agonistbesides its antiserotonergic properties, the D2 agonist apomorphine was also used. Apomorphine caused a dose-dependent increase in proteinintake while carbohydrate and total food intake remained nearly unchanged (0.5 and 1.0 mg/kg i.p., respectively). It is concluded that themesulergine-induced hyperphagic response on both diets is the expression of a dual mode of action, due to its 5-HT2C antagonist activitytogether with D2 agonist properties. The results further indicate that the activation of hypothalamic 5-HT2C receptors may be involved inboth protein sparing and carbohydrate suppressing effects of 5-HT (m-CPP-like effect), whereas an important role in increase of proteinconsumption seems to have the dopaminergic system probably through D2 receptors (apomorphine-like and mesulergine-like effects,respectively).
D 2005 Elsevier Inc. All rights reserved.
Keywords: Apomorphine; Carbohydrate enriched diet; Dietary choices; Dopamine (DA) receptors; D2; Food deprivation schedule; 5-Hydroxytryptamine (5-HT)receptors; 5-HT2C; Isocaloric diets; m-CPP; Mesulergine; Protein enriched diet The serotonergic system has an inhibitory role in appetite behaviour and has been the main target for drug developmentagainst obesity ( Abbreviations: CED, Carbohydrate enriched diet; DA, Dopamine; DMN, Fairburn, 2002; Halford and Blundell, 2000; Leibowitz, 1991; Dorsomedial nucleus of hypothalamus; 5-HT, 5-hydroxytryptamine (serotonin); Simansky, 1996, 1998). Furthermore, there is a close relation- LHA, Lateral area of hypothalamus; m-CPP, 1-(3-chlorophenyl)piperazine;PED, Protein enriched diet; PVN, Paraventricular nucleus of hypothalamus; SB ship between satiety, dietary choices and serotonergic activities 200646, N-(1-methyl-5-indonyl)-NV-(3-pyridyl) urea hydrochloride; SB 242084, 6-chloro-5-methyl-1-[2(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indo- Leibowitz, 1990). Clinical and preclinical studies have shown line; TFI, Total food intake; VMN, Ventromedial nucleus of hypothalamus.
that administration of compounds which enhance serotonergic * Corresponding author. Tel.: +30 210 7462561, +30 210 6822552; fax: +30 neurotransmission (i.e., fenfluramine, fluoxetine and sertraline) E-mail address: sorfeas@otenet.gr (S. Antonatos).
induce hypophagia in both animals and humans ( 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2005.08.018 S. Antonatos, P. Galanopoulou / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 Schreiber, 2000; Garattini et al., 1992; Hewitt et al., 2002; clear that any specific 5-HT receptor subtype mediates the Kitchener and Dourish, 1994; Sargent et al., 1997; Simansky and Vaidya, 1990). Conversely, administration of serotonergic receptor antagonists reducing serotonin (5-HT) activity may The objectives of the present study were threefold. First, to investigate the effects of both the mixed 5-HT2C/1B receptor Schreiber, 2000; Dourish et al., 1989; Fletcher, 1988).
agonist, m-CPP, and the non-selective 5-HT2C antagonist, Cloning and radioligand techniques have allowed the mesulergine, on macronutrient selection. m-CPP is mentioned subdivision of serotonin (5-HT, 5-hydroxytryptamine) recep- to be a 5-HT2C receptor ligand in vivo and its hypophagic tors into 7 distinct families, with each of 14 receptor subtypes effects are mainly, but not exclusively, mediated by agonistic that are recognized at present having its own properties (r et al., 2002). A variety of approaches have suggested that Kaplan et al., 1998; Kennett and Curzon, 1988b; Schreiber concurrent activation of 5-HT2C and 5-HT1B receptors located and De Vry, 2002; Vickers et al., 2003). Specifically, the on hypothalamic sites leads to full expression of serotonergic hypophagic effects of m-CPP are thought to reflect a drug- induced acceleration of satiety processes at low doses (i.e., Importantly, a confluence of evidence supports that 5-HT2C 0.1 – 3.0 mg/kg) and may also involve an inhibition of receptors contribute substantially to the serotonergic suppres- appetitive processes at the same dose range and Schreiber, 2000; De Vry et al., 1999, 2003; Kitchener and Receptor binding studies and functional models in rats have Dourish, 1994). On the other hand, mesulergine has been demonstrated that m-CPP has approximately 10-fold selectivity reported to stimulate food intake in rats and for the 5-HT2C over the 5-HT1B receptor subtype ( Schreiber, 2000; Dourish et al., 1989; Kaplan et al., 1998; 1993; Vickers et al., 2003). Accordingly, m-CPP is considered Kennett and Curzon, 1988b; Schreiber and De Vry, 2002).
a useful probe of 5-HT2C receptor function in both laboratory Second, to assess the precise role of 5-HT2C receptors in macronutrient selection using combined treatment of m-CPP, particular, studies using the mixed 5-HT2C/1B receptor agonist, at its highest effective dose, with mesulergine. A series of m-CPP, indicated that its hypophagic effects in rats are studies have revealed the marked, but not the complete, primarily mediated via activation of 5-HT2C receptors and that blockade of m-CPP-induced hypophagia by the non-selective stimulation of 5-HT1B receptors plays only a minor role in m- Kaplan et al., 1998; Kennett and Curzon, 1988b). Third, to et al., 2002; Kennett and Curzon, 1988a, 1991). Moreover, the clarify the effects of mesulergine on dietary choices given that use of 5-HT receptor antagonists such as mianserin, metergo- this compound produced an unexpected increase in protein line and mesulergine, which show some selectivity for the 5- intake in rats according to our first findings. Consequently, HT2C sites, strongly suggested that the 5-HT2C receptors were we should try apomorphine, a dopamine agonist at D2 largely responsible for mediating the anorectic effects of m- receptors, since mesulergine also possesses dopamine proper- ties at D2 receptors besides its antagonist activity at 5-HT2C 1988a,b, 1991; Prinsen et al., 1996, 2000). The use of more selective 5-HT2C receptor antagonists in recent years, such as poulos et al., 1998). It has been postulated that dopamine SB 200646 and SB 242084, which also caused a remarkable (DA) through D2 receptors located in the lateral hypothalamus blockade of m-CPP-induced hypophagia in rats, have strength- and adjacent areas inhibits markedly or even completely Schwartz et al., 2000; Yang et al., 1997). Systemic Assessment of the effects of serotonin (5-HT) receptor administration of D2 agonists (i.e., apomorphine, lisuride) agonists and antagonists on feeding behaviour has been that reduce dopaminergic neurotransmission led to a substan- generally restricted to measurement of the consumption of solid standard food, i.e., pellets, whereas studies using et al., 1986; Treit and Berridge, 1990). Particularly, dopamine macronutrient or diet selection have been scarce (ry (DA) receptors have been related to the preference of protein and Schreiber, 2000). Unfortunately, diet selection paradigm studies are fraught with methodological problems that in turn diet paradigm was used. These two isocaloric diets were result in a lack of definitive results. Contextual variables, such as quality of the test diets, form/type of macronutrient 1984). Experimental animals were treated under a food- chosen, route of drug administration, acute or chronic deprivation schedule (16 h deprivation and consequently 32 treatment, respectively, nutritional state of the animals, h free access to food) in order to increase feeding motivation deprivation or free feeding protocol, or even the isocaloric value of chosen diets among other things, could have a All compounds and the combined treatment were given immediately prior to a 4-h refeeding period. It has been Leibowitz and Alexander, 1998). Although recent studies reported that the effects of acute administration of a have shown that 5-HT drugs suppress carbohydrate and/or fat compound on ingestive behaviour may be more pronounced intake while sparing protein consumption, it is not yet fully S. Antonatos, P. Galanopoulou / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 Experimental study was performed according to food- deprivation schedule which consists of 16-h food deprivation Male Wistar rats 2 months T 10 days of age and mean body and consequently free access to food for the next 32 weight 210 T 5 g were used. Rats were randomly assigned to treatment groups (usually n = 6 – 8/group) and individually (usually n = 6 – 8 per group) was tested in parallel, always housed in a quiet environment under a normal 12-h light/dark including control group(s) treated with the corresponding period (light on at 8:00 a.m.). Room temperature was vehicle of the particular drug(s) tested. Rats were once tested.
maintained at 21 T1- C and relative humidity at 50 T 15%.
Before testing animals were acclimatized to 3 periods of Animals were allowed free access to a pair of isocaloric diets deprivation-refeeding and received a single injection of enriched in protein or carbohydrate, respectively, and had ad vehicle (0.9% saline) at times corresponding to subsequent drug administration. On the day of the experiment, rats All animal experiments were reviewed and approved by the received a single injection of a particular dose of a given drug local committee and all studies have been carried out in or its vehicle 15 min before the refeeding period. When accordance with the National Institute of Health Guide for the cotreatment was used, the antagonist was given 30 min before Care and Use of Laboratory Animals (NIH Publications No.
testing, i.e., 15 min before the second injection (agonist or 80-23) revised 1996. Effects were made in order to use the saline). Then, animals were given a simultaneous free access minimal amount of rats and reduce their suffering.
to each pair of isocaloric diets. Feeders, which containedpreweighed food, were removed 4 h after the last injection.
Finally, protein (PED) and carbohydrate enriched diet (CED)selected by animals were measured and total food intake m-CPP (1-[3-chlorophenyl]piperazine) was obtained from Research Biochemicals International(Natick, MA). Mesuler- All testing was conducted during the light phase of the cycle gine hydrochloride and apomorphine hydrochloride were purchased from Sandoz Pharma Company, Basle, Switzerland.
All compounds were dissolved in 0.9% saline and wereadministered via the intraperitoneal route in a volume of 1 ml/kg body weight. The doses of all drugs were based on ourprevious tests (unpublished data) and published studies of the For data presentation, food intake was expressed in grams per 4 h of refeeding period and means and S.E.s were calculated et al., 2003; Dourish et al., 1989; Hewitt et al., 2002; Schreiber for all animal groups. For agonist testing (Experiments 1 and 3), and De Vry, 2002; Treit and Berridge, 1990).
data were analysed by a one-way ANOVA with the factor doseand the dependent variable macronutrient intake. For antagonist testing (Experiment 2), data were analysed by a two-wayANOVA with the factors agonist and antagonist and the Animals were singly housed in cages, supported by two dependent variable macronutrient intake. The Tukey HSD test feeders. They were supplied with the following pair of powdered was done for post hoc multiple comparisons with P < .05 isocaloric diets prepared in our laboratory ( considered to indicate statistical significance.
These two diets in their protein and carbohydrate content but fatcontent was held constant. Specifically, protein enriched diet (PED) in feeder A contained 80% casein, whereas carbohydrateenriched diet (CED) in feeder B contained 80% d-glucose with 3.1. Effects of m-CPP on feeding and dietary choices in rats components in both diets are shown in Twerealternated daily to minimize place preference development.
Administration of all three doses of m-CPP (Experiment 1) led to a dose-dependent hypophagia (Specifically, protein consumption was spared while carbohydrate and total Precise proportions of the components in Feeders A and B food intake were significantly suppressed in a dose- dependent manner. All doses of m-CPP were effective in this test. Accordingly, 2.50 mg/kg of m-CPP (maximum effective dose) was selected for the subsequent antagonist study with mesulergine. ANOVA showed a significant effect for agonist on carbohydrate consumption, F(3, 29) = 2.237, P < .001; total food intake, F(3, 29) = 14.146, P < .001. The protein consumption was unaffected by m-CPP, F(3, 29) = PED: protein enriched diet, CED: carbohydrate enriched diet.
S. Antonatos, P. Galanopoulou / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 Mean (S.E.) foodintake (g/4hr)
Treatment (mg/kg , IP)
Fig. 1. Effects of the 5-HT2C/1B receptor agonist, m-CPP, on feeding behaviour and dietary choices at 4-h basis. Rats were deprived of food for 16 h. Data representmean S.E.; n = 8 per group. *P < .05, **P < .01 as compared with the corresponding vehicle-treated group for that particular time period.
3.2. Effects of serotonin antagonist mesulergine on m-CPP- effects induced by m-CPP on carbohydrate and total food induced hypophagia and dietary choices in rats under food- intake were blocked by pretreatment with mesulergine in a Interestingly, mesulergine treatment on its own caused a The results for this experimental testing (Experiment 2) are significant dose-dependent hyperphagia, since a substantial presented in The dose of 2.50 mg/kg of m-CPP increase in both protein and carbohydrate intakes were found induced a significant reduction in carbohydrate and total food with significant increase of total food intake as a consequence.
intake, respectively whereas protein intake remained un- ANOVA indicated a significant interaction effect between the factors agonist and antagonist on protein ingestion, F(5, 42) = Pretreatment with the non-selective 5-HT2C antagonist 23.740, P < .001; carbohydrate ingestion, F(5, 42) = 21.110, mesulergine, dose-dependently reversed m-CPP-induced hypo- P < .001; and total food intake, F(5, 42) = 32.340, P < .001.
phagia during the 4-h test period. In great detail, proteinconsumption was significantly increased while the hypophagic 3.3. Effects of dopamine agonist apomorphine on feeding anddietary choices in rats under food-deprivation schedule The results for this experimental testing (Experiment 3) are 2C receptor antagonist mesulergine on m -CPP- induced hypophagia and macronutrient intakes, respectively, at 4-h basis presented in . Apomorphine, a selective D2 agonist, caused a dose-dependent increase in protein intake whereascarbohydrate and total food intake remained nearly unchanged.
Treatment with mesulergine produced the expected feeding behaviour. According to our findings, mesulergine led to a significant hyperphagia, due to an increased intake of both protein and carbohydrate enriched isocaloric diets.
ANOVA gave a significant effect for Agonist on Protein intake, F(3, 21) = 11.410, P < .001. The carbohydrate and total food intake were unaffected by apomorphine.
2.95 T 0.70**,. 9.90 T 0.25**,. 12.85 T 0.15**,.
A number of studies have demonstrated that the adminis- tration of the mixed 5-HT2C/1B receptor agonist, m-CPP, causes Rats were deprived of food for 16 h. Data represent mean S.E.; n = 8 per group.
a significant hypophagia through a clear serotonin-type action *P < .05, **P < .01 as compared with the corresponding vehicle vehicle-treated group for that particular time period. .P < .05, .P < .01; comparison of obtained in the present food-deprivation protocol replicated the mesulergine m-CPP-treated group with the corresponding vehicle m-CPP- hypophagic effects of m-CPP in a dose-dependent manner.
treated group. All compounds were administered i.p.
Particularly, a substantial decrease in carbohydrate ingestion PED: protein enriched diet, CED: carbohydrate enriched diet, TFI: total foodintake.
was noted without any important influence on protein S. Antonatos, P. Galanopoulou / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 Mean (S.E.) foodintake (g/4hr)
Treatment (mg/kg , IP)
Fig. 2. Effects of the D2 receptor agonist, apomorphine, on feeding behaviour and dietary choices at 4-h basis. Rats were deprived of food for 16 h. Data representmean S.E.; n = 6 per group. *P < .05, **P < .01 as compared with the corresponding vehicle-treated group for that particular time period. 3 mg/kg of the non-selective5-HT2C receptor antagonist with dopaminergic properties, mesulergine, was used as positive control in the apomorphine experimental testing.
consumption. However, it is well known that serotonin (5-HT) al., 1986). Similar effects were also observed with microinjec- and compounds which enhance serotonergic neurotransmis- tion of serotonin into the ventromedial (VMN) and dorsome- sion, like fenfluramine and fluoxetine, induce a reduction in caloric intake attributed to a decrease in carbohydrate and/or fat 1988). Local perfusion of m-CPP into ventromedial hypotha- consumption, while protein intake remains relatively unaffect- lamic nucleus but not into lateral area of hypothalamus (LHA) or frontal cortex, inhibits intake in rats (5- effects of m-CPP are predominantly mediated by agonistic HT2C receptors are expressed in these hypothalamic regions— principally in ventromedial hypothalamic nucleus (VMN)— Kaplan et al., 1998; Kennett and Curzon, 1988b; Schreiber and implicated in the regulation of energy balance ( De Vry, 2002; Vickers et al., 2003). A bulk of studies have Tecott, 2004; Hoffman and Mezey, 1989; Kaplan et al., 1998; recommended a role of 5-HT2C and a lesser extend 5-HT1B Wright et al., 1995). According to our findings in the present receptors in the control of ingestive behaviour ( study, 5-HT2C receptor activation seems to make the major Schreiber, 2000; De Vry et al., 2003; Hewitt et al., 2002). It has contribution to the hypophagic actions of m-CPP. Regarding also been suggested that 5-HT2C knockout mice (mutant mice the pharmacological mechanisms underlying m-CPP-induced lacking functional 5-HT2C receptors) are less sensitive to the hypophagia in the rats, it has been reported that m-CPP has hypophagic effects of m-CPP, supporting the suggestion that 5- little affinity for dopamine (DA) receptors and does not HT2C receptors are involved in the hypophagic effect of m-CPP produce significant alterations to dopaminergic system ( nizzi et al., 1981; Kennett and Curzon, 1988b), which is also in attention has focused on the hypothalamus as the locus of agreement with our neurochemical findings (unpublished data).
serotonetgic effects on feeding. Systemic administration of The above data and results indicate that hypophagic effects of indirect agonists such as d-fenfluramine and fluoxetine m-CPP is mainly mediated by 5-HT2C receptors, especially in increases extracellular hypothalamus serotonin (5-HT) levels carbohydrate suppressing and protein sparing effect of seroto- 2004; Vickers et al., 2001). Microinjections of serotonin into In addition, it is generally accepted that non-selective 5- the paraventricular nucleus (PVN) of hypothalamus have been HT2C receptor antagonists, such as mianserin, metergoline and found to suppress feeding by reducing meal size and feeding mesulergine appear to induce a dose-dependent hyperphagia S. Antonatos, P. Galanopoulou / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 Curzon, 1991; Prinsen et al., 1996, 2000). Consequently, only Vry and Schreiber, 2000; Kaplan et al., 1998; Kennett and Curzon, hyperphagic response on carbohydrate isocaloric diet could be 1988b; Prinsen et al., 1996, 2000). In corroboration of this explained as a single antagonist activity of mesulergine at finding, the hypophagic effect of m-CPP is completely blocked hypothalamic 5-HT2C receptors. On the contrary, the mesu- by low doses of the selective receptor antagonists SB 200646 lergine-induced increase in protein consumption ought to be al., 2002; Kennett et al., 1994, 1997; Vickers et al., 2003).
The relationship between 5-HT and nutrient intake has been questioned. Unfortunately, diet selection paradigm studies arefraught with methodological problems that in turn end in a lack Our previous suggestion is based on the fact that although of definitive results. Contextual variables, such as form/type of apomorphine, produced a weak reduction in total food intake, it macronutrient chosen, caloric value of chosen diet, acute or caused a dose-dependent significant enhancement of protein chronic treatment regime, central or peripheral administration of intake. In fact, a decrease in carbohydrate almost equal to the serotonergic drugs could have a noticeable effect on any increase in protein intake was observed. This could imply a observed results in animal studies ). The role of dopaminergic function in regulating the ratio of protein differing paradigm methodology produced strikingly different to carbohydrate intake. It has recently been postulated using results. Nonetheless, many studies employing the three-choice microdialysis and pharmacological approaches, that the ven- diet selection paradigm have shown uniformly that stimulation trolateral striatum is closely involved in the motor control of of serotonin activity, through either microinjection of 5-HT and 5-HT agonists (i.e., fluoxetine, d-fenfluramine) into the para- Salamone et al., 1993). Furthermore, dopaminergic system ventricular nucleus of the hypothalamus or peripheral adminis- through D2 receptors located in the lateral hypothalamus tration of 5-HT agonists and 5-HT antagonists (i.e., metergoline), (LHA) and the adjacent area of ventrolateral striatum inhibits leads to the selective suppression of carbohydrate consumption with no change in the consumption of protein or fat et al., 1988; Schwartz et al., 2000; Yang et al., 1997), and the al., 2000; Leibowitz et al., 1993; Weiss et al., 1991). In most above mentioned receptors are implicated in the preference of cases, the effects of acute administration of a serotonergic compound on cumulative food consumption over a short time lergine is considered a dopamine (DA) agonist at D2 sites interval (i.e., 30 min – 4 h) was measured in food-deprivation besides its affinity at 5-HT2C receptors ( schedules than in free feeding rats ).
Giannakopoulos, 1999) and this dual mode of its action is in In particular, the design of the studies contained a period of food line with our neurochemical results (unpublished data). So, a deprivation, typically varying between 12 and 23 h, in order to possible explanation is that activation of D2 receptors underlies increase feeding motivation. In our testing session, animals were the potency of mesulergine in increasing protein intake. The treated with a food-deprivation protocol and had a 4-h period results in this study are consistent with our previous findings in free access to a pair of isocaloric diets, which differed in protein free feeding rats treated with mesulergine. Those animals were or carbohydrate proportions but fat levels were held constant.
fed two diets, differing in protein and carbohydrate content, but Our results replicated and extended earlier findings got under not isocaloric, where, a dose dependent increase of PED and total food intake was observed 4 h after its administration It seems likely that hypothalamic 5-HT2C receptors play a dominant, but not the exclusive, role in hypophagic effects of m- both food intake and diet selection elicited by mesulergine in CPP. Specifically, the activation of 5-HT2C receptors is the present study can be also explained as an interaction associated with both protein sparing and carbohydrate suppres- between D2 and 5-HT2C receptors located, at least in part, in sing effects of m-CPP. Although m-CPP is reported to be a potent adjacent hypothalamic areas. Indeed, the use of apomorphine 5-HT2C receptor ligand in vivo, it is finally a mixed 5-HT2C/1B was determinant in explaining the effects of mesulergine on receptor agonist. Therefore, it remains to be confirmed by studies using more selective 5-HT2C receptor agonists. The extend towhich 5-HT2C receptors located in hypothalamic regions 4.2. Antagonism study with mesulergine—potential role for 5- influence energy balance ought to be further investigated.
Concerning hyperphagia induced by mesulergine, the blockadeof 5-HT2C receptors produces a significant increase in carbohy- Pretreatment with mesulergine abolished the hypophagia drate increase, mesulergine led to a substantial enhancement of induced by m-CPP. Such data provide further pharmacological protein intake, attributed to its dopaminergic properties.
support that activation of 5-HT2C receptors induces a suppres-sion of total food intake due to a significant reduction in a carbohydrate ingestion, while protein intake is not altered.
Interestingly, among the most remarkable findings from earlier In the present study, results indicate that mesulergine, a antagonism studies are the marked blockade of m-CPP-induced serotonin (5-HT) antagonist at 5-HT2C sites and dopamine D2 hypophagia by the non-selective 5-HT2C receptor antagonists agonist, leads to food intake and diet selection by a dual mode of action: due to the simultaneous antiserotonergic and S. Antonatos, P. Galanopoulou / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 112 – 119 dopaminergic activity causes hyperphagia, which goes in De Vry, J., Schreiber, R., Daschke, A., Jentzsch, K.R., 2003. Effects of parallel with an increase in CED and PED intake, respectively.
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Merck Poster 800x500_2007-7 17.10.2007 16:49 Uhr Seite 1 New Modified-Release (MR) Prednisone Tablet Shows Sustained Reduction of Morning Stiffness and Interleukin-6 (IL-6) in Patients with Rheumatoid Arthritis (RA). Frank Buttgereit1, Gisela Doering2, Achim Schaeffler3, Stephan Witte3, Jacek Szechinski4, Rieke Alten5. 1Charité University Hospital, CCM, Berlin, Germany; 2Merck KGaA, Darmstadt,

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