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treatment, was ingested for a period of two months. effect, and the task of the elevated plus-maze showed sensitivity to detect the effect. In the chronic por um período de dois meses. ingerida foi sibutramina a crônico, tratamento No efeito. o detectar para sensibilidade sentou apre- elevado cruz em labirinto do tarefa a e ansiolítico, efeito o para positivo controle como ansiedade. na interferem não ratos, em máxima antiobesidade de efeito um produzir para descrita é que os efeitos ansiogênico e ansiolítico dos tratamentos agudo e crônico com a sibutramina em sibutramina ratos a Wistar submetidos à tarefa do labirinto com em cruz elevado. crônico e agudo tratamentos dos ansiolítico e ansiogênico efeitos os Arq Bras Metab. Endocrinol 2010;54/4 S INTRODUCTION Introdução: RESUMO Introduction: ABSTRACT S. Frassetto Silvana ratos em espontânea ansiedade na sibutramina da efeito de Ausência on spontaneous anxietyinrats Absence ofsibutramine effect nalina no sistema nervoso central, aumentando assim o gastoenergético. o assim aumentando nervosocentral, sistema no nalina to da obesidade, uma vez que tem a capacidade de inibir a recaptação de serotonina e noradre- Anxiety; elevated plus-maze; ; sibutramine obesity; plus-maze; elevated Anxiety; Keywords of theofelevated plus-maze. task thesubmitted torats chronicsibutramine intreatmentandwith acute anxiolytic effects of Ansiedade; labirinto em cruz elevado; obesidade; sibutramina obesidade; elevado; cruz em labirinto Ansiedade; Descritores voussystem,thereby increasing energyexpenditure. centralner noradrenalinetheserotoninand inof inhibitthe abilityto the has itsince in rats, did not interfere with anxiety.interferewith not did rats, in treatmentsthestudiedat dose,which describedis producetomaximum a effect anti-obesityof nadas aosefeitosansiolíticoouansiogênico. J. Lopes Janaína butramine is not related to anxiolytic or anxiogenic effects. e ooyrt − iue ) a be dsrbd s a as described been has 1) Figure − monohydrate de - hydrochlori N-dimethylamine N, cyclobutyl]-3methyl agents(1). sity andantidepressant antiobe- as attention special given been have pathways neurotransmitter both Thus, anxiety. and depression obesity,to related symptomatology the in involved are Sibutramine (BTS54524; N-[1-[1(4-chloro phenyl) N-[1-[1(4-chloro (BTS54524; Sibutramine important role in the control of important energy balance, and an play (NA) noradrenaline and (5-HT) erotonin Conclusões: A sibutramina tem sido descrita como um fármaco recomendado para o tratamen- Sibutramine has been described as a drug recommended for treatment of obesity, 2 , A.Paulo Oliveira 1,2 As administrações aguda e crônica de sibutramina não estão relacio- estão não sibutramina de crônica e aguda administrações As , Isis O., Isis Alves Methods: Resultados: Diazepam was positiveusedaas control fortheanxiolytic Conclusions: 2 , Marislane M. Santos ,Marislane 2 , Anapaula S. , Vinagre Anapaula Os tratamentos agudo e crônico, na dose estudada, Arq BrasEndocrinolMetab. 2010;54(4):375-80 The acute and chronicsiandadministration acuteof The Objective: Arq Bras Endocrinol Metab. 2010;54(4):375-80 Métodos: Investigate anxiogenicthe and Results: ced increase in energy expenditure (9). Thus, although Thus, (9). expenditure energy in increase ced ved to be a major of determinant the sibutramine-indu - energy (5-8). locomotion Furthermore, has been obser of expenditure the increasing thus system, nervous tral cen- the in NA and 5-HT of reuptake the of inhibition the that affirmed been has It (2-4). receptors 1-adrenergic alpha and muscarinic histaminic, to affinity without but since it has the ability to inhibit 5-HT and NA reuptake, of obesity, treatment for long-term recommended drug 3 ,E. S.Ana Schmidt 4 , Patrícia Pereira ,Patrícia effects of sibutramine are mediated by the by mediated are sibutramine of effects vivo in O diazepam foi usado The acute and chronic Objetivo: Investigar 3 2 , - - Porto Alegre, RS, Brazil Rio GrandedoSul(UFRGS), Universidade Federal do Canoas, RS, Brazil Ulbra, Canoas,RS, Brazil (Ulbra), Canoas,RS, Brazil Universidade LuteranadoBrazil 4 3 2 1 article original Accepted onJan/20/2010 Received onSept/3/2009 [email protected] 92425-900 − Canoas, RS, Brazil Av. Farroupilha, 8001 Curso de Ciências Biológicas Universidade Luterana do Brasil Silvana S. Frassetto Correspondence to: Departamento deFisiologia, Departamento Curso deMedicina,Ulbra, Curso deFarmácia eBiomedicina, Curso deCiênciasBiológicas, 375 -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. used. They were housed individually in metabolic ca- metabolic in individually housed were They used. 308.7 between weighing colony breeding our from rats Wistar Male Subjects subjects andmethods litic-like effects of reuptake inhibitors(17). reuptake ofserotonin litic-like effects anxyo- the for hypothesis plausible most the as cribed des- been has behavior locomotion-increasing that fact the despite effects, anxiolytic to related not is tramine sibu- of administration chronic and acute that is thesis sibutramine on the elevated plus-maze task. Our hypo- sent paper we evaluated the acute and chronic effects of - pre the In (18). sibutramine with chronically treated motion and in the lower increase in body weight of rats Absence ofsibutramine effect onanxiety 376 Figure 1. Structureofsibutramine. 5-HT by modulated mechanisms the that demonstrated have We status. clinical the describe to and plus-maze, ted eleva- the on tested rats on sibutramine of effects nic (17). of theseotherdrugs those to similar effects locomotor produces anxiolytic in locomotor activity, since diazepam as a rapidly-acting increase the to related probably is inhibitors reuptake serotonin with treatment long-term through anxiety in reduction that observed been has it Thus, (16,17). locomotion increased also have SNRIs and SSRIs ne, sibutrami- with as this, Despite (1,13-15). obesity of treatment the in loss weight sustained achieve to failed have but depression, and anxiety of treatment the in (SNRI) reuptake inhibitors, have been preferred for use serotonin-noradrenaline and (SSRI) serotonin lective leading to its approval as an anti-obesity agent (11,12). trials clinical in obtained been have results promising less (10), sibutramine of effect the ted suppor have data experimentation animal preliminary - chro and acute the investigate to aims study This se- as such agents, nontriclyclic hand, other the On 2 eetr ae novd n h ices o loco- of increase the in involved are receptors C1 19.1g (mean 19.1g ± H 3 C N CH 3 S.E.M., n = 70) were were 70) = n S.E.M., ± CH 3 CH 3 - Lutheran UniversityofBrazil. the of Committee Ethical the by approved was tocol - pro experimental The standards. Health of National Institute by and care, animal for (SBNeC) Behavior and Neuroscience for Society Brazilian the by mended - recom guidelines the with accordance in out carried were procedures experimental All ME/kg). cal. 700 = protein and ME/kg, cal. 485 = fat ME/kg, cal. 1750 = (carbohydrates ME/kg calories 2935 about of (ME) energy metabolizable of consisted rats to given ration normocaloric The 23°C. of temperature constant a at AM) 7.00 at on (lights cycle light/dark 12-h a follo- wing food, and to access controlled with ges, received sibutramine were 134.8sibutramine werereceived who those and rats control in levels Glucose ment. triglyceridestreat afterandglucose plasma of levels the regarding groups between differences no were 301.2 h rcie sbtaie a 346.8 was sibutramine received who ted out in literature for experiments with rats (22,23). thermore, the selected dose reflected the usual dose poin antiobesitymal effect,increasing satietyrats(4).Furin concentrationused has been described to produce maxi 1.1mg/kg/day (mean S.E.M.)± ofthe drug. Thefinal ± 10.4 of concentration a ingested groupsibutramine the Thus, S.E.M.). ± (mean mL/day 4.2 ± 37.2 was intake was measured daily, and the average consumption In the acute treatment, sibutramine (Medley sibutramine treatment, acute the In Drugs andtreatmentprocedure ± sibutramine dissolvedinwater(21). of mg/kg/day 14 received which rats sibutramine: 2) wing groups: 1) control: rats which received water; and day, plus 50 mL of liquid, in accordance with the follo- per food of g 40 given and cages metabolic individual in kept were rats the period experimental the During (4,18). months two of period a over daily rats the to administered was sibutramine treatment chronic the In injection. after minutes thirty task the to subjected separately were animals The effect. anxiolytic the for control positive a as used was Diazepam mL/kg. 1 of tramine (10 mg/kg) (20) intraperitoneally in a volume glycerides in both groups were 44.0 weregroups both glycerides in 8.5 mg/dL (mean zepam (Sigma zepam rats received saline, diazepam (1 mg/kg) (19) mg/kg) (1 diazepam saline, received rats 5.7 mg/dL (mean The final body weight of control rats and those and rats control of weight body final The ± . g (mean g 8.3 ® ) was dissolved in a saline solution. The solution. saline a in dissolved was ) ± S.E.M.), respectively. Plasma tri ± S.E.M.), respectively. ± ..) respectively. There S.E.M), Arq Bras Metab. Endocrinol 2010;54/4 ± 6.8 and 122.4 and 6.8 ± 3.7 and 43.2 and 3.7 ± 09 and g 10.9 ® The fluid ) or dia- or )

or sibu- or ± - - - - -

Arq Bras Metab. Endocrinol 2010;54/4 not induceanxiolyticoranxiogenic effects. suggesting that chronic treatment with sibutramine did arms, enclosed and open the in 0.09) = p 3B; (Figure centage of entries (Figure 3A; p = 0.11) and time spent the per regarding betweenthegroups cant differences sibutramine is shown in figure 3. There were no signifi- with treatment chronic received who received those and who water rats of behavior The group. saline the (p arms open the in 2B) (Figure spent time and 2A) (Figure entries of percentage increased the significantly diazepam hand, other the On shown). not (results task this on effect any show not did mg/kg) (20 concentration Another group. saline to compared 0.13) = p 2B; (Figure arms these in spent time of percentage the and 0.19) = p 2A; (Figure arms didnot alter the percentage of entries in the open and enclosed (10 mg/kg) Sibutramine 2. is figure in treatment shown acute the in sibutramine and saline, diazepam given rats the of task plus-maze elevated The RESULTS program. for Windows SPSS the using performed were tests Statistical cance. p mean as expressed were Student the by analyzed were data treatment, chronic the In test. Duncan’s ANOVAby followed one-way through examined was data maze In the acute treatment, the comparison of elevated plus- Statistical analysis spent in these arms (%Time spent/Total). enclosed arms (%Entries/Total) and percentage of time and open the in entries of percentage as expressed are Results arms. enclosed and open the in spent time the and entries of number the observers: two by recorded 5-minute test period, the following measurements were plus-maze.theDuringa centralofplatform the on ally individuplacedexperiments,chronicanimalswere the were conducted under dim red light. After the acute and 10 cm). The height of the maze was 50 cm, and the tests type were oppositeeach to each other and ofto a platform (10 cm x arms two the that way a such in ranged ar cm), 40 x cm 10 x cm (50 arms enclosed two and apparatusconsisted cm)two10ofopen(50xcm arms anxiety is described in detail elsewhere (24). Briefly, the of models animal in used task plus-maze elevated The Elev 0.05 was considered as indicating statistical signifi- statistical indicating as considered was 0.05 < ated plus-mazetask S.E.M. In the comparison, the In S.E.M. ± ompared to compared 0.05) < -test. The results results The t-test. - - - (16,17).Interestingly, result a anxietyasreductionin a an important role in the increase of locomotor behavior (,playSNRIsduloxetine), also andxamine) suchas SSRIs (citalopran, , , fluvo with sibutramine(18). chronically treated rats in locomotion of increase the in involved ht ehnss ouae b 5-HT by modulated mechanisms that task open-field an of means by demonstrated have Thus, we (9). regulators important are systems NA and 5-HT both where ther cases in locomotion, and mogenesis of increase an to due be may this expenditure, energy in increase the to relation In (12). expenditure energy in increase an energy and satiety, increasing of by intake reduction a mechanism: dual a of conse- quence a as described is sibutramine of effect obesity anti-anti-obesity (11,12).Theagent an as approval its to leading trials, clinical in results promising less with but (22), drug antidepressant an as developed was it sibutramine, of profile pharmacological the regards As (26,28). diseases anxiety-related treating in effective is reuptake NA and 5-HT inhibit which drugs with ment or anxiogenic-like of effects antidepressant drugs. ments are sufficient andreliable for detecting anxiolytic position that elevated plus-maze conventional measure fluoxetine and paroxetine (27). These findings favor the (SNRI) acute of effect anxiogenic the and (26),antidepressant inhibitor reuptake a serotonin-noradrenaline , chronic of effect anxiolytic the tected de has plus-maze elevated the Moreover, laboratory. our in model this of sensitivity the validated diazepam arms are considered as anxiogenic (24). The results with elicit a thatdecrease of drugs the entries hand, and time other spent the in the On open 2B). and 2A (Figures entries and time spent in the open arms being increased anxiolytic-likebehavioral percentage the of with profile an displaythat diazepam as such (25), drugs diazepine detects the anxiolytic of clinically effect relevant benzo 2Aand 2B). Elevated plus-maze is atask which reliably (Figures significant not was difference the but group werelonger inthe sibutramine group than inthe saline arms enclosed the in spent time and entries of centage per the treatment, acute the In 3). (Figure behaviors anxiety-related of expression are the sibutramine with associated with not treatments chronic and acute that showed taskplus-mazeelevated the of results The DISCUSSION Serotoninergic mechanisms of antidepressant agents, - treat chronic that demonstrates evidence Clinical Absence ofsibutramine effect onanxiety 2 receptors are are receptors 377 ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. ht clms oe am. ry oun: nlsd rs * < 0.05 < p * compared tosaline. arms. enclosed columns: Gray arms. open columns: White group). per animals 11-12 = (n S.E.M. ± mean as shown are values The on diazepam or sibutramine with percentage treatment of entries (A) and time spent acute (B) in the open and enclosed of arms. Effect 2. Figure 378 SSRI/5-HT mixed the andamitriptyline) ne, increase locomotor activity, such as (imiprami of antidepressant agents which reduce anxiety but fail to in motor behavior differentiates them from other classes has been observed that this responseit to Furthermore, SSRIs(17). andagent anxiolyticSNRIs an as diazepam with case the is as environment, new a of conditions the under activitylocomotor of increase the to related being as observed is drugs these of use chronic the of B A Absence ofsibutramine effect onanxiety ht ifrn mcaim, rsmby u t 5-HT to due presumably mechanisms, different that indicate models animal in system serotoninergic the of specific no manipulations and Pharmacologic (27,31). others in studies effect some in effects (27,30) like anxiogenic- or (26,29) anxiolytic- produce to reported been has animals in established of tion nists, and (16). % Time spent/Total % Entries/Total Discussing the acute and chronic results, administra- 10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80 0 0 Saline Saline Diazepam Diazepam * * * * Sibutramine Sibutramine 2 antago - - o atvt truh eooiegc ehnss (18). mechanisms serotoninergic through activity tor actionitseven3B),andtoorincreasing3Ain locomo of sibutramine is not related to anxiolytic effects (Figures concludedthatthehave we anxiety,but of treatment long-term the in effective be could tramine of inhibiting serotonin-noradrenaline reuptake by sibu- milnacipran, venlafaxineandduloxetine(37). as such disorder, this of treatment effective an be can (SNRIs) modulating 5-HT and NA system disorder (36). Consequently, it has been described that anxiety of etiology the in role important NA an play and may 5-HT between interaction the addition, In (35). anxiety increased is compounds serotonergic of administration acute of effect initial the that reported been has It (33,34). behaviors anxiety-related of sion - expres the in involved are (32), specificities open arms.Graycolumns:enclosed columns: White group). per animals 17-19 = (n S.E.M. ± mean as shown entries (A) and time spent (B) in the open an enclosed arms. The values are 3. Figure B A % Time spent/Total % Entries/Total In this study, we have hypothesized that the effect effect the that hypothesized have study,we this In 10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80 0 0 Effect of chronic treatment with sibutramine on percentage of percentage on sibutramine with treatment chronic of Effect Control Control Arq Bras Metab. Endocrinol 2010;54/4 Sibutramine Sibutramine

chronicuse -

Arq Bras Metab. Endocrinol 2010;54/4 2. 1. REFERENCES was reported. Disclosure: no potential conflict of interestrelevant to this article for a young researcher scientific initiation program. scholarship a through (Ulbra) Brasil do Luterana Universidade Acknowledgment:this research was sponsored and supported by the characterization and differentiation of these notagents.onlyanxietyon anddepression importantmaybe in nism of activity of antidepressant drugs and their influenceatment of anxiety. In addition, we believe that the mechacluded in a class of SNRIs which are anti-obesitynot effective activity,in the tremakes it possiblemotorbehavior energy(9,18) forandexpenditure with this(9) drug to be in radrenalinereuptake by sibutramine which increases loco ne afterasingleadministration. sibutrami- of effects anxiolytic described (38) cols. and Jorge 2B). and 2A (Figures effects anxiolytic with ted Jorge and cols. (38), the acute treatment is not associa- by incontrasttowhathasbeenreported Furthermore, 11. 10. 9. 8. 7. 6. 5. 4. 3.

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Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 380 34. 33. 32. 31. Absence ofsibutramine effect onanxiety ade S. -yrxtytmn ptwy i axey n its treatment. Pharmacol and Ther. 1995;66(1):103-48. anxiety in pathways 5-Hydroxytryptamine SL. Handley macol Ther. 1995;65(3):319-95. Phar research. of years 30 than more disorders: anxiety of dels mo- animal in drugs 5-Hydroxytryptamine-interacting G. Griebel Psychiatry. 1996;57(6):5-10. Clin J disorders. anxiety in specificity receptor SerotoninLucki I. Sci. 1987;8:383-9. neurotransmission. Pharmacol Trends5-HT modify that pounds P,Chopin M. Briley effectsthe anxiety: of models Animal com- of - 38. 37. 36. 35. Res. 2004;50(5):517-22. Pharmacol rats. in behaviours anxiety-related on sibutramine of Jorge SD, Pobbe RLH, Soares VP, Oliveira AM, Zangrossi H. Effects classes ofantidepressants.CNSSpectr. 2005;10(9):732-47. with other incomparison tolerability and efficacy, clinical logy, pharmaco- their SNRIs: M. Briley C, Moret MM, Grady SM, Stahl cology ofanxiety. JClinPsychiatry. 1999;60(22):12-7. PT.Ninan anatomy,neurochemistry,pharma- functional and The mol Med.2004;5(1):27-40. anxiety.Neuro- R. and Hen JA,system Gordon serotonergic The Arq Bras Metab. Endocrinol 2010;54/4