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Original Papers

DOI: 10.5455/bcp.20130313045200

Evaluating The Antidepressant Efficacy of Aripiprazole Using a Chronic Mild Stress Model: An Experimental Study Ibrahim Eren1, Arif Demirdas2, Ikbal Civi Inanli3

ÖZET:

ABSTRACT:

Giriş: Aripiprazol dopamin D2, D3 ve serotonin 5-HT1A, 5-HT2C, 5-HT7 reseptörlerinin parsiyel agonisti ve serotonin 5-HT2A ve 5-HT6 reseptörlerinin antagonistidir. Parsiyel D2 reseptör agonizmasının mezolimbik ve mezokortikal yolaklarda dopaminerjik nörotransmisyonu stabilize ettiği düşünülmektedir. Dopamin ve serotonin sistemlerindeki düzensizliklerin depresyon etyolojisinde sorumlu tutulan faktörlerden biri olduğu bilinmektedir. Dopamin ve serotonin reseptörleri üzerine etkisi olan aripiprazolün ratlarda antidepresan etkinliğinin araştırılması amaçlanmıştır. Yöntem: Bu çalışmada 8 haftalık Wistar Albino cinsi erkek ratlar kullanıldı. Ratlar her bir grupta sekiz adet olmak üzere 4 gruba ayrıldı. Ratlarda depresyon modeli olarak 4 hafta süreyle Kronik Hafif Stres (KHS) modeli kullanıldı. Birinci grup kontrol grubu olarak alındı. Bu gruba KHS uygulanmadan serum fizyolojik plasebo olarak verildi. İkinci gruba kronik hafif stres (KHS) ile birlikte aripiprazol (2.5mg/kg), 3. gruba KHS ile birlikte essitalopram (10mg/kg), 4. gruba KHS ile birlikte plasebo (serum fizyolojik) verildi. KHS modeli başlamadan önce ve daha sonra haftada bir kez sükroz testi uygulandı. Bulgular: Sükroz tüketimleri başlangıçta ve 1. haftada gruplar arasında farklı değildi. KHS uygulanan grubun sükroz tüketim değerleri 2. 3. ve 4. haftalarda kontrol grubundan anlamlı olarak düşük bulundu. Aripiprazol ve essitalopram alan grubun sükroz tüketimleri başlangıç, 1. ve 2. haftalarda KHS uygulanan gruptan farklı bulunmazken; 3. ve 4. haftada KHS uygulanan gruptan anlamlı olarak yüksek bulundu. Aripiprazol ve essitalopram alan grupların sükroz tüketim değerleri çalışma boyunca kontrol grubundan farklı değildi. Sonuç: Bu çalışmada depresyon modeli oluşturulan ratlarda aripiprazolün essitalopramla karşılaştırılabilir antidepresan etki oluşturduğu gösterilmiştir.

Introduction: Aripiprazole is a partial agonist of dopamine D2 and D3 and serotonin 5-HT1A, 5-HT2C and 5-HT7 receptors, and it is also an antagonist of serotonin 5-HT2A and 5-HT6 receptors. Partial D2 receptor agonism is thought to stabilize dopaminergic neurotransmission in the mesolimbic and mesocortical pathways. Dysregulation in the dopamine and serotonin systems is known to be one of the factors that is responsible for the etiology of depression. In this study, we aimed to evaluate the antidepressant potential of aripiprazole in rats by studying its effects on dopamine and serotonin receptors. Method: In this study, male Wistar Albino rats of 8-week old were used. They were divided into 4 groups, each of which consisted of 8 rats. As a depression model, the Chronic Mild Stress (CMS) model was used for four weeks on the rats. The first group was the control group and that received saline as a placebo without CMS. For the second group, aripiprazole (2.5 mg/kg) was administered with CMS; for the third group, escitalopram (10mg/kg) was administered with CMS and for fourth group a placebo (serum physiologic) was given with CMS. Additionally a sucrose consumption test was performed before and after the CMS model. Results: Sucrose intake at the baseline and within the first week of the study did not differ among the groups. The sucrose consumption of the group with CMS was significantly lower than that of the control group during the second, third and fourth weeks. While the consumption of sucrose in the groups who received aripiprazole and escitalopram did not differ from the group which was exposed to CMS at the beginning and during the first and second weeks, it was significantly higher at the third and fourth weeks. The sucrose consumption values of the groups that received aripiprazole and escitalopram were not different from the control group throughout the study. Conclusion: In this study, aripiprazole has been shown to produce an antidepressant effect comparable to that of escitalopram in rats using a model of depression.

Aripiprazolün antidepresan etkinliğinin kronik hafif stres modeli ile değerlendirilmesi: Deneysel bir çalışma

Anahtar sözcükler: aripiprazol, antidepresan etkinlik, deneysel depresyon, kronik hafif stress

Evaluating the antidepressant efficacy of aripiprazole using a chronic mild stress model: an experimental study

Klinik Psikofarmakoloji Bulteni 2014;24(1):15-22 Keywords: aripiprazole, antidepressant experimental depression, chronic mild stress

effect,

Bulletin of Clinical Psychopharmacology 2014;24(1):15-22

Klinik Psikofarmakoloji Bülteni, Cilt: 24, Sayı: 1, 2014 / Bulletin of Clinical Psychopharmacology, Vol: 24, N.: 1, 2014 - www.psikofarmakoloji.org

1 Assoc. Prof., KonyaTraining and Research Hospital, Department of Psychiatry, Konya - Turkey 2 Assist. Prof., Süleyman Demirel University, Faculty of Medicine, Department of Psychiatry, Isparta - Turkey 3 M.D., KonyaTraining and Research Hospital, Department of Psychiatry, Konya - Turkey

Address reprint requests to: Dr. İbrahim Eren, Konya Eğitim ve Araştırma Hastanesi, Psikiyatri Kliniği, Yazır Mahalesi Turgut Özal Caddesi No:14/D, Selçuklu, Konya - Türkiye Phone: +90-532-486-7588 E-mail address: [email protected] Date of submission: December 05, 2012 Date of acceptance: March 13, 2013 Declaration of interest: I.E., A.D., I.C.I.: The authors reported no conflict of interest related to this article.

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INTRODUCTION Aripiprazole is a novel antipsychotic drug that has a different pharmacological profile from typical and atypical antipsychotics. It is also a new generation, dopamine-balancing antipsychotic drug, which is a partial agonist for dopamine D 2 and D 3, serotonin 5-HT 1A, 5-HT 2C and 5-HT 7 receptors, and antagonist for 5-HT 2A and 5-HT 6 receptors 1-4 . It is considered that partial D2 agonism stabilizes dopaminergic nerve c o m mu n i c a t i o n i n t h e m e s o l i m b i c a n d m e s o c o r t i c a l p a t h w a y s 5. T h e e f f e c t o f aripiprazole resulting in 5-HT 2A receptor blockade and 5-HT 1A receptor stimulation increases dopamine release6. Evidence from human and animal studies suggests that dopamine plays a critical role in the pathophysiology of depression 7,8 and the therapeutic efficacy of antidepressants9,10. The fact that patients with Parkinson’s disease, whose dopaminergic systems have significantly degenerated, are affected by a high incidence of depression (40%) supports the suggestion that dopaminergic system impairment exists in depression11,14. There is evidence of basal ganglia dysfunction from imaging studies of major depressive disorders15. Dopamine plays an important role in basal ganglia function. In studies performed with magnetic resonance imaging (MRI) the signal density of the basal ganglia of depressive patients was found to be higher compared to healthy i n d i v i d u a l s 1 6 . I n a dd i t i o n , s t u d i e s w i t h computerized tomography and MRI have revealed a reduced basal ganglia volume in these patients17,18. In studies with SPECT, low regional blood flow was found in the basal ganglia of depressive patients, while reduced glucose metabolism in the area was showed with PET19. To support this hypothesis, studies which measured homovanilic acid(a metabolite of dopamine) concentrations in cerebrospinal fluid (CSF) of patients with major depression found it to be reduced8,20. In postmortem brain analyses of depression patients who committed suicide, a 16

reduction in the dopamine metabolite, hydroxyphenyl acetic acid, has been reported. These studies support the dopamine abnormality theory of depression21. Aripiprazole has been used in manic and mixed episodes of bipolar disorder and has been found to be effective in this field after being approved for schizophrenia treatment in 2002. Studies have revealed that aripiprazole is effective in schizophrenia, major depressive disorder and manic, depressive and protective treatment of bipolar disorder22,23. It has been shown in several studies that aripiprazole is effective as an augmentation therapy in resistant depression and as add-on therapy in the treatment of major depressive disorder24,25. Although human studies have revealed that antipsychotics are effective in depression, especially when a psychotic component is present, recent studies have indicated that successful antidepressant activity is achieved by aripiprazole in depressive patients without a psychotic component who have had insufficient response to other medications 26,27. In patients with bipolar disorder who were unresponsive to mood stabilizers, aripiprazole was demonstrated to have an antidepressant effect. In metaanalyses of two placebo controlled trials evaluating the efficacy of aripiprazole as monotherapy in bipolar depression, aripiprazole was found to be superior to placebo in the1st and 6 th weeks but no difference was detected in week 828. It has been reported that aripiprazole has shown antidepressant efficacy when administered alone to animals 29 . In animal studies, aripiprazole was found out to enhance antidepressant activity when administered with antidepressants except for bupropion and desipramine30. In this study, it is considered that aripiprazole is a dopamine system regulator that should be efficacious in depression treatment. Its effects on the dopaminergic system play a crucial role and thus we aimed to investigate aripiprazole’s efficacy in rats.


Eren I, Demirdas A, Civi-Inanli I

MATERIALS AND METHODS

Materials

Experimental Animals

Methods and Principles Regulations published in the official gazette number 26220 on 6 July 2006 by the Turkish Government Ministry of Forestry and Water Affairs.

In this study 32 male Wistar Albino rats with a weight of 200±15 g were used. The rats were adapted to the environment one week prior to the experiment. The rats were kept in separate plastic cages with beds. They could reach standard rat food and tap water. To get accustomed to the taste of sucrose, they were provided with sucrose (1%) for one week before the procedure. Cage temperature was held at 22±2ºC. The light-dark cycle was established as twelve hours of daylight and 12 hours of darkness by switching the lights on at 06:00 am and off at 06:00 pm. The rats were assigned to 4 groups of eight. Aripiprazole and escitalopram was administered orally diluted in saline. The first group (n=8) was the control group and saline (in an equivalent amount given orally) was used without Chronic Mild Stress (CMS). For the second group (n=8), aripiprazole (2.5 mg/kg) was administered with CMS; for the third group (n=8), escitalopram (10 mg/kg) was administered with CMS and for the fourth group (n=8) (the depression group) saline with CMS was administered. The rats were housed individually. Homogeneous distribution among the groups was provided. The study was performed in accordance with the Helsinki Declaration and Animal Experiments Ethical Committees’ Study

Chronic Mild Stress Model

The chronic mild stress (CMS) model is a wellvalidated rat model of core depressive symptoms 31,32 . In this model, the rats are continuously exposed to various types of relatively mild stress. These stressors include leaving the rats without water and then putting an empty water bottle into the cage, lighting the cage continuously, sloping the cage, separating the cages, making the floor of the cage wet with 300cc water, implementing a 90 db noise and switching the lights on and off at 300 times a minute. These stressors are applied for several hours alternately and lasted for weeks or months31. The applied procedures of CMS may be seen in Table 1.

Sucrose Consumption Test

The sucrose consumption test was applied to rats before the CMS started. The sucrose test is used to measure anhedonia which is described as the decrease in sucrose consumption when compared to control and starting values. Sucrose consumption in an hour after 20 hours of hunger was investigated at the begining. The results were recorded as basal values. All results were calculated in mililiters. The sucrose consumption test was

Table 1: Chronic Mild Stress (CMS) Model

Sunday

Leaving waterless

16:00 →

08:00

08:00-09:00

16:00 →

08:00

11:00-17:00

Giving empty water bottle Lightening the cage continuously Sloping the cage Separating the cages

Monday

Tuesday

Wednesday

→ → →

08:00

Wetting the beds (300cc)

90 DB noise

11:00-16:00

Switching lights on and of continuously

Thursday

Friday

Saturday

17:00 → 10:00

18:00 → 14:00 10:00 →→→ 17:00 → 10:00

10:00-13:00

13:00-15:00


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different among the groups. The sucrose consumption of the group where CMS was applied was significantly lower in the second, third and fourth weeks compared to the control group. In the aripiprazole administered group, sucrose consumption values were not different in the first and second weeks while they were significantly higher in the 3rd and 4th weeks compared to the CMS group. In the aripiprazole group sucrose consumption was not different from the control group for the entire time. In the escitalopram group, sucrose consumption values were not different at the beginning or in the first and second weeks but they were significantly higher in the third and fourth weeks compared to CMS group. Also in the escitalopram group sucrose consumption was not different from the control group for the whole study. When the sucrose consumption values of the aripiprazole and escitalopram groups were compared, no difference was detected for the

repeated on the fourth day of each week at 12:00 pm for four weeks and the results were recorded. The CMS phase was then held. This process was repeated for four weeks33.

Statistical Analyses

Statistical analyses were performed using the “SPSS 13.0 for Windows” pocket program. Intergroup differences were investigated with the Kruskal-Wallis test of variance analysis. Two groups’ comparisons were performed by the Mann-Whitney U test. P values under 0.05 were accepted to be significant.

RESULTS

Sucrose Consumption Test Results

In our study, the rats’ sucrose consumption at the beginning and after the first week was not Table 2: Sucrose consumption test results Basal 1. week 2. week 3. week 4. week

Group I Group II Group III Group IV (Control) (ARI+CMS) (ES+CMS) (CMS) Mean±SD (ml) Mean±SD (ml) Mean±SD (ml) Mean±SD (ml) 4.38±177 8.13±5,08 8.88±3.18 9.75±4,71 8.63±3.46

4.13±1,13 4.13±2.10 7.88±5.41 4.88±2.90 5.38±4.96 8.88±5.11 8.14±2,48 10.88±4,45 8.43±3.04 9.75±2.66

z

p

4.38±1,51 0.83 0.84a 4.25±1.75 3.66 0.30a 4.38±2,62 6.64 0.08d,f,g 2.88±1,46 16.52 0.001b,c,d,e,f,g 2.63±1.06 17.00 0.001b,c,d,e,f,g

CMS: Chronic Mild Stress, ARI: Aripiprazole, ES: Escitalopram, SD: Standard Deviation a) No significant difference between all groups b) No significant difference between aripiprazole and escitalopram groups c) Aripiprazole group is significantly higher than CMS group (z =-3.21, p