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Signature: Med Sci Monit, 2002; 8(10): BR385-390 Fluoxetine differentially suppresses sucrose solution consumption in free-fed and food-deprived rats– reversal by amantadine Mark A. Prendergast1,2 abcdefg, David P. Yells1,2 abcde, Scott E. Balogh2 ade, Stephen R. Paige2 acde, Shelton E. Hendricks1,2 abcdefg C Statistical AnalysisD Data Interpretation 1 Department of Psychology, University of Nebraska at Omaha, NE, USA 68182 2 Department of Psychiatry, University of Nebraska, NE, USA 68198 Clinical use of fluoxetine and similar medications is often associated with appetite suppressionand weight loss that may warrant drug discontinuation. It is unclear, however, if fluoxetine-induced consummatory suppression may be influenced by factors such as dietary status and ifappetite suppressant effects of fluoxetine may be pharmacologically attenuated.
Fluoxetine (0.5–10 mg/kg, i.p.) was administered to free-fed and 24 hr food-deprived adultmale rats either 30 min or 4 hr prior to presentation of a sucrose solution (10% v/v). Further,amantadine (5–10 mg/kg, i.p.) and fluoxetine (5 mg/kg) were both administered either 30 minor 4 hr prior to sucrose solution presentation and intake of the solution was assessed after 2hours of exposure.
Fluoxetine (2–10 mg/kg) administration significantly reduced sucrose solution intake in bothfree-fed and food-deprived rats. However, a brief treatment-test interval (30 min) resulted ina greater suppression of intake and food-deprived rats were more resistant to the suppressanteffects of fluoxetine than were sated rats. Finally, the suppressant effect of fluoxetine werereversed by acute administration of amantadine (8 mg/kg) prior to sucrose solution presenta-tion, a dose producing no inherent stimulation of consumption.
Acute fluoxetine administration produces a reduction in palatable substance intake that isdecreased in potency with a longer treatment-test interval, an effect likely not related to phar-macokinetic considerations. Further, fluoxetine-induced consummatory suppression isreduced by prior food-deprivation. Evidence that the dopamine agonist amantadine reversedfluoxetine-induced consummatory suppression suggests a role for dopaminergic antagonismin the appetite suppressant effects of fluoxetine.
appetite • serotonin • feeding • food-deprivation http://www.MedSciMonit.com/pub/vol_8/no_10/2683.pdf Dr. Mark A. Prendergast, 115 Kastle Hall, Department of Psychology, University of Kentucky, Lexington, KY, 40506-0044 USA Pharmacological manipulations which facilitate central Experiment 1
or peripheral serotonin (5-HT) activity suppress feedingin humans [1] and rats [2–4]. Systemic [5] or central [6,7] administration of 5-HT decreases consumption ofstandard lab chow. Similarly, systemic administration of One-hundred adult-male rats (300–400 g) derived in- indirect pharmacologic 5-HT agonists such as fluoxetine house from Sprague-Dawley rats (Sasco, Omaha, NE) (FLX) and dexfenfluramine has been shown to reduce were used with five rats in each group. Rats were ho- intake of a cornstarch diet [8], standard lab chow [9] used in wire mesh cages with two rats per cage and ma- and sweetened liquid and solid diets [7,10,11]. In fact, intained under controlled conditions of light (on at appetite suppression has been cited as a factor that con- 1900 h and off at 0900 h) and temperature (22–24°C).
tributes to the discontinuation of clinical use of 5-HT Water and standard lab chow were available ad libitum agonists such as FLX and similar selective serotonin reuptake inhibitors in a significant number of depressedpatients [12].
While considerable neurochemical and anatomical At 1300 h of the day prior to testing (24 h prior to te- evidence indicates a significant role for 5-HT activity, sting), lab chow was removed from the cages of one-half particularly in diencephalic regions, in the suppres- of the rats. At 0900 h or 1230 h of the day of testing (4 sion of feeding, some confusion exists concerning the hrs or 30 min prior to testing, respectively) each rat re- specific nature of this suppression. Several researchers ceived an injection (ip) of FLX HCl (0.5, 2, 5, or 10 have demonstrated the ability of 5-HT agonists to se- mg/kg) dissolved in vehicle (distilled H O) or vehicle lectively suppress consumption of foods which are alone. All injections were administered in a volume of 2 high in carbohydrate content and low in protein con- cc/kg. At 1300 h of the day of testing rats were placed tent [13,14]. Others have demonstrated a selective ro- individually in wire mesh test cages (15 × 25 × 15 cm).
le for 5-HT agonism in suppressing fat intake [15,16].
They were then given access for 2 hours to a water bot- Such evidence has been interpreted as suggesting that tle containing 100 ml of a 10% wt/v sucrose/distilled 5-HT mediation of feeding is based on the availability H O solution. Weights of the filled water bottles were of CNS neurotransmitters, their amino acid precur- recorded prior to and immediately after testing. For sors, or other dietary nutrients [2,17]. Consistent with each rat, the difference between pre- and post-test water this is evidence that, in sated animals, synthesis and bottle weights was calculated and expressed as a percen- release of 5-HT are highly sensitive to local brain con- tage of an individual rat’s pre-test body weight to con- centrations of tryptophan and are altered rapidly by trol for potential differences in baseline consumption dietary restriction [18–20]. This suggests that manipu- related to differences in body weights.
lations which decrease CNS levels of 5-HT and the 5-HT amino acid precursor tryptophan, such as 24 hrs Experiment 2
of food-deprivation [21], may alter the influence ofhypophagic agents on feeding. Specifically, Leander [13] has suggested that food-deprived animals may bemore resistant than sated animals to the hypophagic Sixty adult-male (300–400 g) derived in-house from influence of 5-HT agonists, because of this putative Sprague-Dawley rats (Sasco, Omaha, NE) were used state of CNS 5-HT deprivation. This suggestion has with five rats in each group. Rats were housed and ma- not, however, been empirically examined in signifi- intained as in Experiment 1 with the exception that fo- The present studies examined the relationship betwe- en feeding status and the effects of FLX on sucrosesolution consumption. Patterns of palatable liquid so- At 0900 on the day of testing (4 hrs prior to testing), lution consumption closely approximate those of so- one-half of the rats were injected with either FLX (5 lid foods in rats and are sensitive to alterations in 5- mg/kg) dissolved in vehicle or vehicle alone. At 1230 HT activity in a similar manner [13]. In addition, h on the day of testing (30 min prior to testing), these FLX possesses no inherent ability to suppress intake rats were injected again with vehicle or AMA (5, 8, 10, of water, indicating that changes in sucrose solution or 20 mg/kg). At this same time (1230 h), the remaining consumption are not associated with hypodypsia [13].
rats received an injection of either vehicle or FLX (5 These studies also examined the extent to which hy- mg/kg) followed immediately by an injection of either pophagia induced by FLX administration may be at- vehicle or AMA (5, 8, 10, or 20 mg/kg). All injections we- tenuated by amantadine, a compound with significant re administered as described in Experiment 1. At 1300 dopaminergic agonist properties [18,22], providing h of the same day, rats were placed individually in wire data which may be particularly relevant to clinical use mesh test cages and given access for 2 hrs to 100ml of fluoxetine and other selective serotonin reuptake a 10% wt/v sucrose solution. Consumption of the solu- tion was measured as previously described.
Prendergast MA et al – Fluoxetine differentially suppresses sucrose solution… Figure 1. Dose-dependent effects of fluoxetine, administered 30 min
prior to testing, on the sucrose solution consumption of free-fed and 24 hr food-deprived rats. Data represent mean % Figure 3. Effect of FLX (5 mg/kg) alone and in combination with AMA
body weight consumed ± s.e.m. * p<0.01 vs controls; (5–20 mg/kg) on sucrose solution consumption. Both FLX and AMA were administered 30 min prior to behavioral test-ing. Data represent mean ± s.e.m. *p<0.05 vs controls that animals treated with 2, 5, or 10 mg/kg of FLX con-sumed significantly less of the sucrose solution than didrats treated with vehicle (p<0.05). A reduction in con-sumption of greater than 50%, as compared to controls,was observed with each of these doses. In 24 hr food-de-prived rats, pretreatment with only the 5 and 10 mg/kgdoses of FLX produced similar, significant suppressionof consumption (p<0.05).
The dose-dependent effects of FLX administered 4 hrsprior to testing on sucrose solution consumption are il-lustrated in Figure 2. A significant interaction betweenfeeding status and dose of FLX was observed [F(4, 40)= 5.11, p<0.01]. Post hoc analyses indicated that, as Figure 2. Dose-dependent effects of fluoxetine, administered 4 hrs
when administered 30 min prior to testing, pretreat- prior to testing, on the sucrose solution consumption of free- ment with the 2, 5, or 10 mg/kg doses of FLX significan- fed and 24 hr food-deprived rats. Data represent mean % tly reduced consumption of the solution by free-fed rats, body weight consumed ± s.e.m. * p<0.01 vs controls; compared to consumption by rats which received the vehicle pretreatment (p<0.05). With the two higher do-ses (5 and 10 mg/kg), consumption was nearly complete-ly suppressed relative to controls, by 80% and 78%, re- Statistical Analysis
spectively. In food-deprived rats, animals which rece-ived only the highest dose of FLX (10 mg/kg) consumed Data were analyzed by use of two-way analyses of va- significantly less solution (16% of controls) than did tho- riance treating feeding status and treatment as separate se which received vehicle (p<0.01). The 5 mg/kg dose factors in Experiment 1 and time of administration and of FLX, which suppressed consumption when admini- treatment as separate factors in Experiment 2. Where stered 30 min prior to testing, failed to significantly al- appropriate, multiple post hoc analyses were conducted ter consumption when administered 4 hrs prior to te- Experiment 2
Experiment 1
Figure 3 illustrates the dose-dependent effects of AMA,administered to free-fed rats 30 min prior to testing, on The dose-dependent effects of FLX administered 30 hypophagia induced by FLX (5 mg/kg), also administe- min prior to testing on sucrose solution consumption in red 30 min prior to testing. A significant effect for drug food-deprived and free-fed rats are illustrated in Figure treatment was observed [F(5, 23) = 2.83, p<0.05]. Post 1. A significant interaction between feeding status and hoc analysis indicated that rats which received vehicle in- drug treatment was observed [F(4, 40) = 3.71, p<0.05].
jections only 30 min prior to testing consumed significan- In free-fed rats, multiple post hoc comparisons indicated tly more solution than did those which received the com- acutely, dose-dependently suppresses food intake infree-fed and food-deprived rats [8,11,13]. However,a higher minimal dose of FLX was necessary to suppressconsumption in deprived rats than in sated rats. Thissupports the suggestion that the influence of FLX onconsumption of palatable foods may be significantly al-tered by the feeding status of subjects and possible alte-rations in CNS 5-HT levels [13]. However, a role fornon-5-HT systems in this hypophagic-like effect can notbe discounted, particularly given evidence that doses offluoxetine required to produce hypophagia are greaterthan those that produce inhibition of 5-HT reuptake[23]. These data may suggest the interaction of fluoxeti-ne with other transmitter receptor systems in producinghypophagia. However, this greater resistance of food-deprived rats to the hypophagic effects of a 5-HT ago-nist is consistent with similar results reported using the Figure 4. Effect of FLX (5 mg/kg) alone and in combination with AMA
5-HT precursor, 5-HTP [24], leading to the suggestion (5–20 mg/kg) on sucrose solution consumption. FLX was that use of free-fed animals may represent a more sensi- administered 4 hrs prior testing. All doses of AMA were tive means of detecting the acute anorectic properties of administered 30 min prior to testing. Data represent mean % drugs. Further, several reports indicate that 24 hrs or body weight consumed ± s.e.m. *p<0.05 vs controls longer of food deprivation in rat results in decreased le-vels of tryptophan, 5-HT, and 5-hydroxyindoleaceticacid in whole brain homogenate [3,25], diencephalon binations of FLX/Vehicle; FLX/AMA (5 mg/kg), [21], and raphe homogenate [26]. These latter two re- FLX/AMA (8 mg/kg); or FLX/AMA (20 mg/kg) (p<0.05).
gions, and certainly many other regions, are widely tho- Animals which received FLX/vehicle administrations 30 ught to mediate the effects of 5-HT agents on feeding min prior to testing consumed approximately 40% less of [27,28]. The relative lack of effectiveness of FLX in sup- the sucrose solution than did vehicle-treated controls. In pressing consumption in deprived rats seen in the pre- contrast, FLX-induced reductions in consumption were sent study, may well result from deprivation-induced reversed by administration of the 10 mg/kg dose of AMA depletion of 5-HT presynaptic stores and the attenuated 30 min prior to testing. These rats consumed an average amount of the solution nearly identical to that consumedby controls (4.70±0.90 vs. 4.94±1.10% body weight, re- When administered 4 hrs prior to testing, FLX dose-de- spectively). Administration of 5, 8, or 20 mg/kg of AMA pendently suppressed consumption in free-fed rats, as did not effect FLX-induced hypophagia. Interestingly, when administered 30 min prior to testing. A dissimilar when administered 30 min prior to testing in conjunction pattern of FLX’s time-dependent effect on consumption with a vehicle administration, this dose of AMA (10 was observed in food-deprived rat, however. A dose of mg/kg) did not increase consumption of the solution rela- FLX (5 mg/kg), which when administered 30 min prior tive to controls(data not shown), suggesting the lack of an to testing significantly suppressed consumption depri- inherent ability of this dose to alter intake of the solution.
ved rats, had no apparent effect on such consumptionwhen administered 4 hrs prior to testing. A minimal do- The dose-dependent effects of AMA, administered 30 se of 10 mg/kg was necessary to suppress the consump- min prior to testing, on hypophagia in sated rats indu- tion in food-deprived rats. Evidence suggesting that ced by FLX (5 mg/kg) administered 4 hrs prior to te- FLX, at 5 mg/kg and higher doses, is effective in sup- sting are illustrated in Figure 4. A significant effect of pressing the reuptake of 5-HT for several hours follo- drug treatment (vehicle vs FLX vs AMA) was observed wing administration indicates that the increased resi- [F(5, 23) = 4.66, p<0.01]. Post hoc analysis indicated stance of food-deprived rats to the hypophagic effects of that rats which received vehicle both 4 hrs and 30 min FLX administered 4 hrs prior to testing is not associated prior to testing consumed significantly more solution with decreased pharmacologic activity of FLX [29]. The- than did those which received the combinations of se data may suggest that the effects of FLX on feeding FLX/vehicle; FLX/AMA 5 mg/kg; FLX/AMA 10 mg/kg; may be qualitatively distinct when administered 30 min or FLX/AMA 20 mg/kg (p<0.05). However, FLX-indu- ced hypophagia was significantly attenuated by admini-stration of 8 mg/kg of AMA. This dose of AMA, when The results of Experiment 2 demonstrate the ability of administered concurrently with only a vehicle injection, the DA releaser and reuptake inhibitor AMA to attenu- did not exhibit any inherent ability to increase con- ate or reverse hypophagia induced by FLX. At each ti- me point, the reversal of hypophagia produced byamantadine treatment was produced by only one dose of the drug (8 or 10 mg/kg). Higher doses of the AMAdid not similarly reverse FLX-induced hypophagia.
The results of the present study are consistent with pre- While it is unclear as to why dose-dependence was not vious evidence indicating that FLX, when administered observed in this effect, it may reflect actions of AMA at Prendergast MA et al – Fluoxetine differentially suppresses sucrose solution… other receptor sites not affected by the 8 or 10 mg/kg ver, this conclusion remains speculative without detailed doses. It is of particular significance to note that when examination of the immediate and protracted effects of administered alone, those doses of AMA that reversed FLX on central and peripheral 5-HT activity. In addi- consumption deficits induced by FLX, did not increase tion, the lesser sensitivity of acute hypophagia to AMA consumption of the sucrose solution. Increased con- may also be the associated with uncharacterized drug sumption, relative to FLX-treated controls, in rats tre- ated with the combination of FLX and AMA may not beascribed, therefore, to an inherent hyperphagic/hyper- dipsic effect of AMA. These data suggest, then, thatFLX-induced hypophagia is associated, at least in part, In sum, these data suggest that when examining the ef- with a reversible attenuation of DA activity, though fects of FLX and other 5-HT agonists on feeding, the other pharmacologic effects of AMA on NE, cholinergic, treatment-test interval is a critical methodological varia- and/or glutamatergic (ie. N-methyl-D-aspartate recep- ble which can interact with feeding status to mediate the tors) systems, can not be discounted in this regard. The effects of 5-HT activity on feeding. Careful considera- selectivity of AMA in reversing FLX-induced hypopha- tion of such temporal variables and of feeding status is gia via DA agonism is, however, suggested by evidence essential in attempting to examine the effects of FLX, that DA release and reuptake inhibition is the primary and other 5-HT agonists, on feeding. The present study pharmacologic action of AMA [18]. This is also sugge- also demonstrated the ability of AMA to attenuate, and sted by evidence that FLX suppresses DA release in fo- in some cases completely reverse, hypophagia induced rebrain regions (eg. accumbens and striatum) involved by FLX administration. This finding suggests that AMA, in the mediation of feeding [30]. In addition, nucleus and possibly other DA agonists, may possess clinical effi- accumbens administration of a DA antagonist has been cacy in attenuating severe appetite suppression or re- shown to block feeding induced by the pharmacologic striction, such as that induced by 5-HT agonists or obse- attenuation of 5-HT release [31]. As a whole, these data rved in clinical syndromes thought to reflect CNS 5-HT suggest an antagonism between 5-HT and DA systems Acknowledgments
Reversal or attenuation of FLX-induced hypophagia byAMA was evident when FLX was administered to free- The authors wish to thank Eli Lilly Laboratories for the- fed rats either 4 hrs or 30 min prior to testing. Howe- ir donation of fluoxetine HCl. In addition, the authors ver, animals appeared to be more sensitive to reversibili- thank the members of the Psychopharmacology Rese- ty by AMA when FLX was administered 4 hrs prior to arch Center and the Department of Psychiatry at the testing. At this time interval, hypophagia induced by University of Nebraska Medical Center for their aid in FLX was attenuated by the 8 mg/kg dose of AMA. Ho- the preparation of this manuscript. Portions of this wever, when FLX was administered 30 min prior to te- work were supported by a grant (NSF # OSR92-55225) sting, as was AMA, this dose of AMA did not effect FLX- awarded to the Nebraska Behavioral Biology Group of induced hypophagia. A higher dose of AMA (10 mg/kg) The University of Nebraska and Creighton University.
was necessary to reverse hypophagia. This increased re-sistance to AMA suggests that the acute effects of FLX on consumption may have been more profound thanthe protracted effects. Data from Experiment 1 also sup- 1. McGuirk J, Silverstone T: The effect of the 5-HT re-uptake port this contention in that FLX suppressed consump- inhibitor fluoxetine on food intake and body weight in healthy tion in food-deprived rats at a lower dose (5 mg/kg vs 10 male subjects. Int J Obes, 1990; 14: 361-372 mg/kg) when it was administered 30 min prior to te- 2. Blundell JE: Is there a role for serotonin (5-hydroxytryptamine) in sting, as opposed to 4 hrs prior to testing. This resistan- 3. Curzon G, Joseph MH, Knott PJ: . Effects of immobilization and ce is likely not the result of greater activity of FLX at food deprivation on rat brain tryptophan metabolism. J Neu- central 5-HT synapses 30 min after administration gi- ven evidence that central 5-HT reuptake inhibition does 4. Curzon G, Gibson EL, Oluyomi AO: Appetite suppression by com- not reach maximal levels for 3-4 hours after administra- monly used drugs depends on 5-HT receptors but not on 5-HTavailability. Trends in Pharm Sc, 1997; 18: 21-25 tion of a 10 mg/kg dose [32] and that FLX and/or nor- 5. Fletcher PJ, Yu PH: Enhancement of 5-HT-induced anorexia: a FLX may be maximally active in suppressing presynap- test of the reversibility of monoamine oxidase inhibitors. Psy- tic 5-HT reuptake 4 hrs after administration [29]. It is possible, therefore, that the difference may be associated 6. Fletcher PJ, Paterson IA: A comparison of the effects of tryptamine with an acute and selective peripheral effect of FLX on and 5-hydroxytryptamine on feeding following injection into the 5-HT activity and feeding [33-35]. FLX has been shown paraventricular nucleus of the hypothalamus. Pharmacol BiochemBehav, 1989; 32: 907-911 in this laboratory to induce a potent conditioned taste 7. Weiss S, Papadakos P, Knudson et al: Medial hypothalamic sero- aversion to a sucrose solution, indicating the drug’s abi- tonin: effects on deprivation and norepinephrine-induced eating.
lity to induce an aversive state likely related to gastroin- Pharmacol Biochem Behav, 1986; 25: 1223-1230 testinal effects [36]. If a non-specific aversive effect of 8. Luo S, Li ETS: Food intake and selection pattern of rats treated FLX was induced soon after peripheral administration, with dexfenfluramine, fluoxetine, and RU 24969. Brain Res Bull,1990; 24: 729-733 the resultant hypophagia would not be expected to be 9. Weiss S, Rogacki N, Fueg A et al: Impact of hypothalamic d-fenflu- as easily reversed by AMA as would hypophagia induced ramine and peripheral d-fenfluramine injection on micronutrient by a more protracted drug treatment schedule. Howe- intake in the rat. Brain Res Bull, 1990; 25: 849-859 10. Cooper SJ, Dourish CT, Barber DJ: Fluoxetine reduces food intake 24. Blundell JE, Latham CJ: Serotonergic influences on food intake: by a cholecystokinin-independent mechanism. Pharmacol Biochem effects of 5-hydroxytryptophan on parameters of feeding behavior in deprived and free-feeding rats. Pharmacol Biochem Behav, 11. Leander JD: Fluoxetine suppresses palatability-induced ingestion.
25. Perez-Cruet J, Tagliamonte A, Tagliamonte P et al: Changes in 12. Lejoyeux M, Ades J: Antidepressant discontinuation: a review of brain serotonin metabolism associated with fasting and satiation.
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