Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice
João Pedro Costa-Nunes1,2,3, Anastassia Bakhmet4, Margarida Araújo-Correia3,5, Andreia Barbosa Valença3,6, Tatyana Strekalova1,3, Harry W. M. Steinbusch1
1 School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht NL 6229 ER, the Netherlands;
2 Center for Neuroscience and Cell Biology, Universidade de Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, Coimbra 3004-504, Portugal;
3 Centro de Biologia Ambiental, Faculdade de Ciências da Universidade de Lisboa, Edifício C2, Campo Grande, Lisbon 1749-016, Portugal;
4 Department of Human Anatomy, Moscow State Medical University, Moscow 125009, Russia;
5 Centro de Estudos de Doenças Crónicas(CEDOC), Edifício CEDOC II, Rua Câmara Pestana, n°6-6 A, Lisboa, Lisbon 1150-082, Portugal;
6 Centro Interdisciplinar de Investigação em Saúde Animal(CIISA), Faculdade de Medicina Veterinária, Alameda da Universidade Técnica, Lisboa, Lisbon 1300-477, Portugal
Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice
João Pedro Costa-Nunes1,2,3, Anastassia Bakhmet4, Margarida Araújo-Correia3,5, Andreia Barbosa Valença3,6, Tatyana Strekalova1,3, Harry W. M. Steinbusch1
1 School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht NL 6229 ER, the Netherlands;
2 Center for Neuroscience and Cell Biology, Universidade de Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, Coimbra 3004-504, Portugal;
3 Centro de Biologia Ambiental, Faculdade de Ciências da Universidade de Lisboa, Edifício C2, Campo Grande, Lisbon 1749-016, Portugal;
4 Department of Human Anatomy, Moscow State Medical University, Moscow 125009, Russia;
5 Centro de Estudos de Doenças Crónicas(CEDOC), Edifício CEDOC II, Rua Câmara Pestana, n°6-6 A, Lisboa, Lisbon 1150-082, Portugal;
6 Centro Interdisciplinar de Investigação em Saúde Animal(CIISA), Faculdade de Medicina Veterinária, Alameda da Universidade Técnica, Lisboa, Lisbon 1300-477, Portugal
摘要 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.
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.
通讯作者:
João Pedro Costa-Nunes, E-mail:jp.nunes@cnc.uc.pt
E-mail: jp.nunes@cnc.uc.pt
引用本文:
João Pedro Costa-Nunes, Anastassia Bakhmet, Margarida Araújo-Correia, Andreia Barbosa Valença, Tatyana Strekalova, Harry W. M. Steinbusch. Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice[J]. 临床转化神经科学, 2016, 2(3): 172-182.
João Pedro Costa-Nunes, Anastassia Bakhmet, Margarida Araújo-Correia, Andreia Barbosa Valença, Tatyana Strekalova, Harry W. M. Steinbusch. Effects of voluntary imipramine intake via food and water in paradigms of anxiety and depression in naïve mice. Translational Neuroscience and Clinics, 2016, 2(3): 172-182.
20161117200058 Figure 1 Study flow. Time is expressed in days, relative to treatment period (D). Behavioral tests: OM—O-maze; DLB—Dark/light box; ST—Sucrose test; NC—Novel cage; OF—Open field; FST—Forced swim test. Number of animals: Control, n = 7; Imipramine (food), n = 8; Imipramine (water), n = 8.
20161117200126 Table 1 Nutritional composition of standard diet
20161117200326 Figure 2 Antidepressant-like effects of imipramine in the forced swim test. In comparison with control group and animals treated with imipramine in drinking water, mice that received imipramine in food pellets exhibit increased latency to float (a) and reduced total duration of floating (b). *P < 0.05 vs control; **P < 0.01 vs control; ***P < 0.001 vs control; &P < 0.01 vs. imi-food or imi-drink; #P < 0.001 vs imi-food or imi-drink; aP < 0.05 vs baseline. Data are represented as mean ± standard error of mean (SEM). Number of animals: Control, n = 7; Imipramine (food), n = 8; Imipramine (water), n = 8.
20161117200501 Figure 3 Effects of imipramine on anxiety-like behaviour. No significant differences were found in latency (a, b), number of exits (c, d), or time spent in exposed area (e, f) in both dark/light box and O-maze, respectively. aP < 0.05 vs same group, t test. Data are represented as mean ± standard error of mean (SEM). Number of animals: Control, n = 7; Imipramine (food), n = 8; Imipramine (water), n = 8.
20161117200618 Figure 4 Effects of imipramine on basal parameters of locomotor activity. In the open field test, no differences were found in distance travelled (a), average speed of locomotion (b), or number of line crossings (c) between groups. Increased number of rearings is found in the novel cage test for animals receiving treatment in water, when compared to a control group (d). Sucrose preference is not different between control and imipramine-treated groups (e). Data are represented as mean ± standard error of mean (SEM). Number of animals: Control, n = 7; Imipramine (food), n = 8; Imipramine (water), n = 8.
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