Journal Home > Volume 2 , Issue 3
Brain Science Advances 2016, 2(3): 172-182 https://doi.org/10.18679/CN11-6030_R.2016.021
Original Article | Open Access | Issue | Published: 01 September 2016

Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice

Show Author's Information João Pedro Costa-Nunes1,2,3( ),  Anastassia Bakhmet4,  Margarida Araújo-Correia3,5,  Andreia Barbosa Valença3,6,  Tatyana Strekalova1,3,  Harry W. M. Steinbusch1
School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht NL 6229 ER, the Netherlands
Center for Neuroscience and Cell Biology, Universidade de Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, Coimbra 3004-504, Portugal
Centro de Biologia Ambiental, Faculdade de Ciências da Universidade de Lisboa, Edifício C2, Campo Grande, Lisbon 1749-016, Portugal
Department of Human Anatomy, Moscow State Medical University, Moscow 125009, Russia
Centro de Estudos de Doenças Crónicas (CEDOC), Edifício CEDOC II, Rua Câmara Pestana, nº6-6A, Lisboa, Lisbon 1150-082, Portugal
Centro Interdisciplinar de Investigação em Saúde Animal (CIISA), Faculdade de Medicina Veterinária, Alameda da Universidade Técnica, Lisboa, Lisbon 1300-477, Portugal
Keywords:
depression, anxiety, pre-clinical models, oral dosing, animal welfare
Cite this article:
Costa-Nunes JP, Bakhmet A, Araújo-Correia M, et al. Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice. Brain Science Advances, 2016, 2(3): 172-182. https://doi.org/10.18679/CN11-6030_R.2016.021
Download citation
EndNote(RIS)
BibTeX

346

Views

8

Downloads

Citations

0

Crossref

N/A

WoS

N/A

Scopus

N/A

CSCD

Abstract Full text About this article
Objective:

We sought to investigate the efficacy of oral dosing in mice with imipramine (7mg/kg/day) via water or in food pellets, and to compare its effects in the paradigms of learned helplessness, locomotion, hedonic state, and anxiety.

Methods:

Water and food consumption were measured to determine daily imipramine dosage in C57BL/6N mice. Next, baseline scores for O-maze, dark/light box, and sucrose tests were measured. Mice were then subjected to a 4-week treatment of voluntary ingestion of drinking water or food pellets containing imipramine. Lastly, all groups were subjected to novel cage, open field, O-maze, dark/light box, sucrose test, and forced swim test to assess the effects of the treatment.

Results:

In naïve mice, imipramine delivered via food, induced a reduction of total floating and increased latency in the forced swim test, i.e., antidepressant-like effects. No other significant effects were found. Dosing with water did not change behavior in the forced swim, sucrose preference test, anxiety, or locomotor paradigms, but increased exploration in the novel cage.

Conclusions:

Voluntary ingestion is an effective method of chronic dosing with imipramine in naïve mice. Delivery of imipramine with food pellets elicits antidepressant-like effects in the forced swim test, with no effects on anxiety, locomotion, or preference behaviors. In contrast, no such effects were observed with treatment via drinking water, suggesting that a higher dose may be required. Our work argues for a broader use of oral delivery using food-treated pellets, in small rodent models of pre-clinical depression. It may substantially improve animal welfare and overcome potential confounds in translational research, which are frequently associated with adverse chronic invasive pharmacotherapies.


menu
Abstract
Full text
Outline
About this article

Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice

Show Author's information João Pedro Costa-Nunes1,2,3( ), Anastassia Bakhmet4, Margarida Araújo-Correia3,5, Andreia Barbosa Valença3,6, Tatyana Strekalova1,3, Harry W. M. Steinbusch1
School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht NL 6229 ER, the Netherlands
Center for Neuroscience and Cell Biology, Universidade de Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, Coimbra 3004-504, Portugal
Centro de Biologia Ambiental, Faculdade de Ciências da Universidade de Lisboa, Edifício C2, Campo Grande, Lisbon 1749-016, Portugal
Department of Human Anatomy, Moscow State Medical University, Moscow 125009, Russia
Centro de Estudos de Doenças Crónicas (CEDOC), Edifício CEDOC II, Rua Câmara Pestana, nº6-6A, Lisboa, Lisbon 1150-082, Portugal
Centro Interdisciplinar de Investigação em Saúde Animal (CIISA), Faculdade de Medicina Veterinária, Alameda da Universidade Técnica, Lisboa, Lisbon 1300-477, Portugal

Abstract

Objective:

We sought to investigate the efficacy of oral dosing in mice with imipramine (7mg/kg/day) via water or in food pellets, and to compare its effects in the paradigms of learned helplessness, locomotion, hedonic state, and anxiety.

Methods:

Water and food consumption were measured to determine daily imipramine dosage in C57BL/6N mice. Next, baseline scores for O-maze, dark/light box, and sucrose tests were measured. Mice were then subjected to a 4-week treatment of voluntary ingestion of drinking water or food pellets containing imipramine. Lastly, all groups were subjected to novel cage, open field, O-maze, dark/light box, sucrose test, and forced swim test to assess the effects of the treatment.

Results:

In naïve mice, imipramine delivered via food, induced a reduction of total floating and increased latency in the forced swim test, i.e., antidepressant-like effects. No other significant effects were found. Dosing with water did not change behavior in the forced swim, sucrose preference test, anxiety, or locomotor paradigms, but increased exploration in the novel cage.

Conclusions:

Voluntary ingestion is an effective method of chronic dosing with imipramine in naïve mice. Delivery of imipramine with food pellets elicits antidepressant-like effects in the forced swim test, with no effects on anxiety, locomotion, or preference behaviors. In contrast, no such effects were observed with treatment via drinking water, suggesting that a higher dose may be required. Our work argues for a broader use of oral delivery using food-treated pellets, in small rodent models of pre-clinical depression. It may substantially improve animal welfare and overcome potential confounds in translational research, which are frequently associated with adverse chronic invasive pharmacotherapies.

Keywords: depression, anxiety, pre-clinical models, oral dosing, animal welfare

References(57)

[1]
Munos B. Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov 2009, 8(12): 959–968.
DOI Google Scholar
[2]
Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: Current status of research. Psychother Psychosom 2010, 79(5): 267–279.
DOI Google Scholar
[3]
Araragi N, Lesch KP. Serotonin (5-HT) in the regulation of depression-related emotionality: Insight from 5-HT transporter and tryptophan hydroxylase-2 knockout mouse models. Curr Drug Targets 2013, 14(5): 549–570.
DOI Google Scholar
[4]
Insel TR. From animal models to model animals. Biol Psychiatry 2007, 62(12): 1337–1339.
DOI Google Scholar
[5]
Insel TR, Sahakian BJ, Voon V, Nye J, Brown VJ, Altevogt BM, Bullmore ET, Goodwin GM, Howard RJ, Kupfer DJ, et al. Drug research: A plan for mental illness. Nature 2012, 483(7389): 269.
DOI Google Scholar
[6]
Strekalova T, Anthony DC, Dolgov O, Anokhin K, Kubatiev A, Steinbusch HMW, Schroeter C. The differential effects of chronic imipramine or citalopram administration on physiological and behavioral outcomes in naïve mice. Behav Brain Res 2013, 245: 101–106.
DOI Google Scholar
[7]
Costa-Nunes JP, Cline BH, Araújo-Correia M, Valença A, Markova N, Dolgov O, Kubatiev A, Yeritsyan N, Steinbusch HW, Strekalova T. Animal models of depression and drug delivery with food as an effective dosing method: Evidences from studies with Celecoxib and Dicholine succinate. Biomed Res Int 2015, 2015: 596126.
DOI Google Scholar
[8]
Strekalova TV, Cespuglio R, Koval’zon VM. Depressive-like state and sleep in laboratory mice. Zh Vyssh Nerv Deiat Im I P Pavlova 2008, 58(6): 728–737.
Google Scholar
[9]
Strekalova T, Couch Y, Kholod N, Boyks M, Malin D, Leprince P, Steinbusch HMW. Update in the methodology of the chronic stress paradigm: Internal control matters. Behav Brain Funct 2011, 7: 9.
DOI Google Scholar
[10]
Strekalova T, Steinbusch H. Factors of reproducibility of anhedonia induction in a chronic stress depression model in mice. In: Mood and Anxiety Related Phenotypes in Mice: Characterization Using Behavioral Tests. Gould TD, Ed. New Jersey: Humana Press, 2009, pp 153–176.
DOI
[11]
Strekalova T, Steinbusch HWM. Measuring behavior in mice with chronic stress depression paradigm. Prog Neuropsychopharmacol Biol Psychiatry 2010, 34(2): 348–361.
DOI Google Scholar
[12]
Sato Y, Seo N, Kobahashi E. The dosing-time dependent effects of intravenous hypnotics in mice. Anesth Analg 2005, 101(6): 1706–1708.
DOI Google Scholar
[13]
Munn E, Bunning M, Prada S, Bohlen M, Crabbe JC, Wahlsten D. Reversed light-dark cycle and cage enrichment effects on ethanol-induced deficits in motor coordination assessed in inbred mouse strains with a compact battery of refined tests. Behav Brain Res 2011, 224(2): 259–271.
DOI Google Scholar
[14]
Strekalova T, Spanagel R, Dolgov O, Bartsch D. Stress-induced hyperlocomotion as a confounding factor in anxiety and depression models in mice. Behav Pharmacol 2005, 16(3): 171–180.
DOI Google Scholar
[15]
Ringgold KM, Barf RP, George A, Sutton BC, Opp MR. Prolonged sleep fragmentation of mice exacerbates febrile responses to lipopolysaccharide. J Neurosci Methods 2013, 219(1): 104–112.
DOI Google Scholar
[16]
Cloutier S, Wahl K, Baker C, Newberry RC. The social buffering effect of playful handling on responses to repeated intraperitoneal injections in laboratory rats. J Am Assoc Lab Anim Sci 2014, 53(2): 168–173.
Google Scholar
[17]
Bohlen M, Hayes ER, Bohlen B, Bailoo JD, Crabbe JC, Wahlsten D. Experimenter effects on behavioral test scores of eight inbred mouse strains under the influence of ethanol. Behav Brain Res 2014, 272: 46–54.
DOI Google Scholar
[18]
Sorge RE, Martin LJ, Isbester KA, Sotocinal SG, Rosen S, Tuttle AH, Wieskopf JS, Acland EL, Dokova A, Kadoura B, et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods 2014, 11(6): 629–632.
DOI Google Scholar
[19]
Sousa N, Almeida OF, Wotjak CT. A hitchhiker’s guide to behavioral analysis in laboratory rodents. Genes Brain Behav 2006, 5 Suppl 2: 5–24.
DOI Google Scholar
[20]
Azar TA, Sharp JL, Lawson DM. Heart rates of male and female Sprague-Dawley and spontaneously hypertensive rats housed singly or in groups. J Am Assoc Lab Anim Sci 2011, 50(2): 175–184.
Google Scholar
[21]
Gärtner K, Büttner D, Döhler K, Friedel R, Lindena J, Trautschold I. Stress response of rats to handling and experimental procedures. Lab Anim 1980, 14(3): 267–274.
DOI Google Scholar
[22]
Cloutier S, Newberry RC. Use of a conditioning technique to reduce stress associated with repeated intra-peritoneal injections in laboratory rats. Appl Anim Behav Sci 2008, 112(1–2): 158–173.
DOI Google Scholar
[23]
Thiele TE, Navarro M. “Drinking in the dark” (DID) procedures: A model of binge-like ethanol drinking in non-dependent mice. Alcohol 2014, 48(3): 235–241.
DOI Google Scholar
[24]
Machado-Vieira R, Baumann J, Wheeler-Castillo C, Latov D, Henter ID, Salvadore G, Zarate CA Jr. The timing of antidepressant effects: A comparison of diverse pharmacological and somatic treatments. Pharmaceuticals (Basel) 2010, 3(1): 19–41.
DOI Google Scholar
[25]
Yan HC, Cao X, Das M, Zhu XH, Gao TM. Behavioral animal models of depression. Neurosci Bull 2010, 26(4): 327–337.
DOI Google Scholar
[26]
Krishnan V, Nestler EJ. Animal models of depression: Molecular perspectives. In: Molecular and Functional Models in Neuropsychiatry. Hagan JJ, Ed. Berlin Heidelberg: Springer, 2011, pp 121–147.
DOI
[27]
Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985, 85(3): 367–370.
DOI Google Scholar
[28]
Steru L, Chermat R, Thierry B, Mico JA, Lenegre A, Steru M, Simon P, Porsolt RD. The automated Tail Suspension Test: A computerized device which differentiates psychotropic drugs. Prog Neuropsychopharmacol Biol Psychiatry 1987, 11(6): 659–671.
DOI Google Scholar
[29]
Teste JF, Pelsy-Johann I, Decelle T, Boulu RG. Anti-immobility activity of different antidepressant drugs using the tail suspension test in normal or reserpinized mice. Fundam Clin Pharmacol 1993, 7(5): 219–226.
DOI Google Scholar
[30]
Bai FJ, Li X, Clay M, Lindstrom T, Skolnick P. Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 2001, 70(2–3): 187–192.
DOI Google Scholar
[31]
Castagné V, Porsolt RD, Moser P. Early behavioral screening for antidepressants and anxiolytics. Drug Dev Res 2006, 67(9): 729–742.
DOI Google Scholar
[32]
Castagné V, Porsolt RD, Moser P. Use of latency to immobility improves detection of antidepressant-like activity in the behavioral despair test in the mouse. Eur J Pharmacol 2009, 616(1–3): 128–133.
DOI Google Scholar
[33]
O’Neill MF, Fernández AG, Palacios JM. GR 127935 blocks the locomotor and antidepressant-like effects of RU 24969 and the action of antidepressants in the mouse tail suspension test. Pharmacol Biochem Behav 1996, 53(3): 535–539.
DOI Google Scholar
[34]
Azima H. Imipramine (Tofranil): A new drug for the depressed. Can Med Assoc J 1959, 80(7): 535–540.
Google Scholar
[35]
Grecksch G, Zhou D, Franke C, Schröder U, Sabel B, Becker A, Huether G. Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: Behavioural correlates. Br J Pharmacol 1997, 122(8): 1725–1731.
DOI Google Scholar
[36]
Winterhoff H, Spengler B, Christoffel V, Butterweck V, Löhning A. Cimicifuga extract BNO 1055: Reduction of hot flushes and hints on antidepressant activity. Maturitas 2003, 44 Suppl 1: S51–S58.
DOI Google Scholar
[37]
Kaminsky BM, Bostwick JR, Guthrie SK. Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother 2015, 49(7): 808–817.
DOI Google Scholar
[38]
Cline BH, Anthony DC, Lysko A, Dolgov O, Anokhin K, Schroeter C, Malin D, Kubatiev A, Steinbusch HW, Lesch KP, et al. Lasting downregulation of the lipid peroxidation enzymes in the prefrontal cortex of mice susceptible to stress-induced anhedonia. Behav Brain Res 2015, 276: 118–129.
DOI Google Scholar
[39]
Markova N, Chernopiatko A, Schroeter CA, Malin D, Kubatiev A, Bachurin S, Costa-Nunes J, Steinbusch HM, Strekalova T. Hippocampal gene expression of deiodinases 2 and 3 and effects of 3, 5-diiodo-L-thyronine T2 in mouse depression paradigms. Biomed Res Int 2013, 2013: 565218.
DOI Google Scholar
[40]
Costa-Nunes J, Zubareva O, Araújo-Correia M, Valença A, Schroeter CA, Pawluski JL, Vignisse J, Steinbusch H, Hermes D, Phillipines M, et al. Altered emotionality, hippocampus-dependent performance and expression of NMDA receptor subunit mRNAs in chronically stressed mice. Stress 2014, 17(1): 108–116.
DOI Google Scholar
[41]
Cline BH, Steinbusch HWM, Malin D, Revishchin AV, Pavlova GV, Cespuglio R, Strekalova T. The neuronal insulin sensitizer dicholine succinate reduces stress-induced depressive traits and memory deficit: Possible role of insulin-like growth factor 2. BMC Neurosci 2012, 13: 110.
DOI Google Scholar
[42]
Malatynska E, Steinbusch HWM, Redkozubova O, Bolkunov A, Kubatiev A, Yeritsyan NB, Vignisse J, Bachurin S, Strekalova T. Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression. Exp Gerontol 2012, 47(8): 552–564.
DOI Google Scholar
[43]
Nunes J. Behavioural effects of chronic administration of imipramine in food and water regarding anxiety and depression paradigms on naïve C57BL/6N male mice. M.Sc. Dissertation, University of Lisbon, Lisbon, Portugal, 2011.
[44]
Delini-Stula A, Mikkelsen H, Angst J. Therapeutic efficacy of antidepressants in agitated anxious depression—A meta-analysis of moclobemide studies. J Affect Disord 1995, 35(1–2): 21–30.
DOI Google Scholar
[45]
Erburu M, Cajaleon L, Guruceaga E, Venzala E, Muñoz-Cobo I, Beltrán E, Puerta E, Tordera RM. Chronic mild stress and imipramine treatment elicit opposite changes in behavior and in gene expression in the mouse prefrontal cortex. Pharmacol Biochem Behav 2015, 135: 227–236.
DOI Google Scholar
[46]
Ramirez K, Sheridan JF. Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive-like behaviors. Brain Behav Immun, in press, .
DOI Google Scholar
[47]
Enginar N, Hatipoğlu I, Firtina M. Evaluation of the acute effects of amitriptyline and fluoxetine on anxiety using grooming analysis algorithm in rats. Pharmacol Biochem Behav 2008, 89(3): 450–455.
DOI Google Scholar
[48]
Mogi K, Shimokawa Y, Nagasawa M, Kikusui T. Effects of sex and rearing environment on imipramine response in mice. Psychopharmacology (Berl) 2012, 224(1): 201–208.
DOI Google Scholar
[49]
Sorregotti T, Mendes-Gomes J, Rico JL, Rodgers RJ, Nunes-de-Souza RL. Ethopharmacological analysis of the open elevated plus-maze in mice. Behav Brain Res 2013, 246: 76–85.
DOI Google Scholar
[50]
Baek IS, Park JY, Han PL. Chronic antidepressant treatment in normal mice induces anxiety and impairs stress-coping ability. Exp Neurobiol 2015, 24(2): 156–168.
DOI Google Scholar
[51]
Abernethyl DR, Divoll M, Greenblatt DJ, Harmatz JS, Shader RI. Absolute bioavailability of imipramine: Influence of food. Psychopharmacology (Berl) 1984, 83(1): 104–106.
DOI Google Scholar
[52]
Pottenger LH, Domoradzki JY, Markham DA, Hansen SC, Cagen SZ, Waechter JM Jr. The relative bioavailability and metabolism of bisphenol A in rats is dependent upon the route of administration. Toxicol Sci 2000, 54(1): 3–18.
DOI Google Scholar
[53]
Volvert ML, Seyen S, Piette M, Evrard B, Gangolf M, Plumier JC, Bettendorf L. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol 2008, 8: 10.
DOI Google Scholar
[54]
Mombereau C, Gur TL, Onksen J, Blendy JA. Differential effects of acute and repeated citalopram in mouse models of anxiety and depression. Int J Neuropsychopharmacol 2010, 13(3): 321–334.
DOI Google Scholar
[55]
Carr GV, Lucki I. The role of serotonin receptor subtypes in treating depression: A review of animal studies. Psychopharmacology (Berl) 2011, 213(2–3): 265–287.
DOI Google Scholar
[56]
Cryan JF, Sweeney FF. The age of anxiety: Role of animal models of anxiolytic action in drug discovery. Br J Pharmacol 2011, 164(4): 1129–1161.
DOI Google Scholar
[57]
Ihne JL, Fitzgerald PJ, Hefner KR, Holmes A. Pharmacological modulation of stress-induced behavioral changes in the light/dark exploration test in male C57BL/6J mice. Neuropharmacology 2012, 62(1): 464–473.
DOI Google Scholar
Publication history
Copyright
Acknowledgements
Rights and permissions

Publication history

Received: 12 July 2016
Revised: 10 July 2016
Accepted: 24 August 2016
Published: 01 September 2016
Issue date: September 2016

Copyright

© The authors 2016.

Acknowledgements

We would like to thank Dr. Cláudia Oliveira from the CBA and Mrs. Margarida Rama for technical support.

Rights and permissions

This article is published with open access at www.TNCjournal.com

Return