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Effects of two antidepressant drugs on spatial memory performance in rats--experimental research.

BACKGROUND

Affective disorders are frequent disturbances that may affect elderly persons, largely influencing their quality of life. Literature data show that depressive diseases in older adults are usually accompanied by various degrees of cognitive impairment (1). The complex treatment of geriatric depression includes pharmacotherapy and nonpharmacologic procedures (e.g. psychoterapy, cognitive-behavioural methods, interpersonal therapies) (2). The farmacologic treatment of affective disorders in elderly patients consist of selective serotonin reuptake inhibitors and also serotonin and norepinephrine reuptake inhibitors, offering the advantage of a favourable balance between risk and therapeutic benefit (3).

The N-methyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy]propan-1-amine derivative fluoxetine is a selective serotonin reuptake inhibitor used in depression or obsessivecompulsive personality disorder in adults. Reboxetine (a-ariloxybenzyl derivative of morpholine) is a norepinephrine reuptake inhibitor and also a norepinephrine transporter inhibitor, indicated in the therapy of unipolar depression, in panic and attention deficit hyperactivity disorders (4).

WORKING HYPOTHESIS

The findings of various experimental studies suggests the interrelations between norepinephrine and serotonin pathways and affective disorders, revealing that no-repinephrine system is involved in the memory for novel stimuli while some serotonin receptors subtypes mediate the control of recognition memory retrieval (5) (6). To directly verify this hypothesis we investigated the effects of two antidepressant drugs, fluoxetine and reboxetine, on spatial memory performance in the T-maze assay, a behavioural test for measuring the natural tendency of lab animals to explore new environment (7).

The purpose of our study was to evaluate the behavioural effects of the antidepressant drugs fluoxetine and reboxetine on cognitive functions in old rats.

MATERIAL AND METHOD

The experiment was carried out on Wistar male old rats (aged 18 months). During the experiment the animals were housed in polycarbonate cages, at a temperature of 23 [+ or -] 1[degrees]C and a 12-hour dark cycle (light period: 07:00-19:00), with free access to water and standard granulated food. Before the experiment the animals were placed on a raised wire mesh, under a clear plastic box and allowed 2 hours to acclimate to the testing room.

The rats were distributed into 3 groups of 6 animals each, treated orally, during 1 month, as follows:

Group I (Control): saline solution 0,3 ml/ 100 g weight;

Group II (FLX): fluoxetine 10 mg/kbw; Group III (RBX): reboxetine 5 mg/kbw.

The drugs--fluoxetine and reboxetine (purchased from Sigma-Aldrich Chemical Company)--were extemporaneously dissolved in 0.9% saline solution. All the experiments were performed during the same time interval (between 8:00 a.m. to 2:00 p.m.).

To assess the influence of the chosen antidepressants in cognitive functions, the present study evaluated the effects of fluoxetine and reboxetine on rat exploratory behaviour on the T-maze apparatus. This device consists of 3 identical arms (40 x 9 x 16 cm), shaped as the 'T' letter. Each arm has particularly designed walls on the inside surface, allowing animals to distinguish one from the others.

This experimental model was used to assess lab animal working and reference memory by monitoring the rat tendency to explore a new environment, consisting of its preference to visit a new arm of the maze rather than a just explored one (7).

Each animal was first placed in the start arm and allowed to move freely through the maze during an 8 min session. The first 2 minutes were for habituation, and the last 6 minutes for the alternation between arms. After a few seconds the animal chooses between entering either the left or the right arm of the T-maze. Normally, after repeated sessions of experimentation, the rat should choose to explore the alternate arm, manifesting less tendency to enter an arm that was least occupied recently (8). Latency to leave the start arm, latency of first arm visit, number of arms visited, alternate arm returns, and the same arm returns were also investigated.

The alternation percentage was calculated according the formula: number of alternations/total number of arm visits--2 (9). Supplementary, the experiment was videotaped using a video camera connected to a computer in another room, allowing analysis of the animal behaviour without distress.

The data were presented as +/- standard deviation, and significance was determined using the SPSS Program for Windows version 13.0, with the ANOVA one-way method and Newman-Keuls test as post-hoc. P-values less than 0.05 were considered statistically significant compared to Control groups.

The study protocol was approved by the Ethics Committee of Research of "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, in accordance with the actual European legislation. For ethical considerations the duration of the experiments was kept as short as possible, each animal was used once only and immediately sacrificed at the end of the experiment (10).

RESULTS AND DISCUSSIONS

Typically the animal remembers which arm it has just visited, and enters into the different other arm, this being considered a correct choice. Correct arm visiting consists of entering at least the first third part of an arm. The alternation behaviour represents the consecutive entries into each of the three arms (7).

[FIGURE 1 OMITTED]

Chronic administration of fluoxetine (10 mg/kbw) was associated with a slight increase of arms entries number (mean [+ or -] S.E.M. number of arm entries = 16.22 [+ or -] 1.32), but statistically non-significant compared to control old animals (15.39 [+ or -] 2.17) in the T-maze test (Fig. 1).

Oral treatment with reboxetine (5 mg/ kbw), during 1 month resulted in an increase of arms entries number (21.14 [+ or -] 1.20), statistically significant (p < 0.05) compared to saline solution group (15.39 [+ or -] 2.17). The results suggest that reboxetine generated an increase of the performance in this behavioural experimental model in rats (Fig. 1).

Spontaneous alternation in rats refers to animal natural tendency to spontaneously choose alternate arms in the T-maze assay (9). The alternation percentage of Control group was 35.14 [+ or -] 1.63.

The comparative analysis of the results revealed a minor increase in spontaneous alternation rate after fluoxetine administration (36.55 [+ or -] 2.19), but statistically nonsignificant compared to the group treated with saline solution (35.14 [+ or -] 1.63) in the T-maze test (Fig. 2).

Statistical processing of data showed that the treatment with reboxetine (5 mg/kbw) was associated with an increase of spontaneous alternation percentage (43.37 [+ or -] 1.63), statistically significant (p < 0.05) compared to Control group (35.14 [+ or -] 1.63) in the same experimental behavioural model. These data suggest a facilitation of extinction learning capacity, especially on shortterm spatial memory in old rats (Fig. 2.).

[FIGURE 2 OMITTED]

No markedly differences in the latency to leave the start arm and the latency of first arm visit were found between groups treated with fluoxetine, reboxetine and saline solution.

In our experimental conditions, chronic administration of reboxetine, but not of fluoxetine determined an improvement of spatial memory acquisition and also an increase of rat normal spontaneous locomotor activity in the T-maze test. Our previous studies revealed that some antidepressant drugs such as paroxetine, venlafaxine, duloxetine, citalopram and bupropion, but not fluvoxamine improve spatial memory acquisition in old rats in the Y-maze assay (11) (12) (13).

Previous reports have described the effects of some antidepressant drugs in different behavioural models, but most of them are controversial.

One experimental investigation has shown that the selective serotonin reuptake inhibitor paroxetine and the selective norepinephrine reuptake inhibitor reboxetine improved the cognitive deficit in passive avoidance test in animals with memory impairment determined by scopolamine administration. In the same experimental behavioural model the tricyclic antidepressant amitriptyline did not prove to have evident influence on memory deficit, effect probably related to its anticholinergic action (14).

Others researches have demonstrated that reboxetine improves the recognition memory without affecting the locomotor activity in the forced swim test in rats (15) (16). Opposite to this, other findings suggest that some antidepressants such as fluoxetine, venlafaxine can impair the spatial memory in a variant of Y-maze test in rats (which are not capable to recognise the arm with changed brightness), while reboxetine does not significant interfere the animal spatial memory performance in the same behavioural model, probably due to the lack of influence on the serotonin level (17).

A large comparative study between antidepressant drugs has revealed their various effects on cognitive functions, actions that are related to the neurotransmitters involved. Thus, both type of antidepressants: the noradrenaline reuptake inhibitors (reboxetine, atomoxetine), and the serotonin-noradrenaline reuptake inhibitor (duloxetine), improved the recognition memory, while the tricyclic antidepressants (desipramine, mianserin) or the serotonin reuptake inhibitors (paroxetine, citalopram) did not significant influence the recognition memory in various behavioural models in rats (5).

CONCLUSIONS

Using the classic behavioural experimental model T-maze test, we demonstrated an enhancement of spatial memory in the rats treated with the norepinephrine reuptake inhibitor reboxetine, but not with the selective serotonin reuptake inhibitor fluoxetine, highlighted by an increase of spontaneous alternation percentage compared to Control animals, which suggests significant effects on short-term memory.

In our experimental conditions the administration of antidepressant reboxetine during 1 month was associated with the improvement of cognitive performances and the facilitation of the exploratory locomotor activity in old rats, this drug being more efficient in facilitating extinction learning.

AKNOLEDGEMENT AND DISCLOSURE

The authors have no potential conflict of interests to disclose.

REFERENCES

(1.) Blazer, D. G., Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci 2003, 58(3):249-65.

(2.) Ishak, W. W., Ha, K., Kapitanski, N. et al, The impact of psychotherapy, pharmacotherapy, and their combination on quality of life in depression. Harv Rev Psychiatry, 2011, 19(6):277-89.

(3.) Birrer, R. B., Vemuri, S. P., Depression in Later Life: A Diagnostic and Therapeutic Challenge. Am Fam Physician 2004, 69(10):2375-2382.

(4.) Katsung, B. G., Trevor, A. J., Basic & Clinical Pharmacology, 13th Edition 2015, Mc Grow Hill Education, Lange, Section V, Chapter 30.

(5.) Feltmann, K., Konradsson-Geuken, A., De Bundel, D. et al., Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats. Behavi Neurosci 2015, 129(6): 701-708.

(6.) Zhang, G., Stackman, R. W., The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 2015; 6: 225.

(7.) Baker, M., Animal models: Inside the minds of mice and men. Nature 2011, 475, 123-128.

(8.) Burgess, N., Spatial cognition and the brain. Ann New York Acad Sci 2008, 1124, 77-97.

(9.) Hughes, R. N., The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosc Biobehav Rev 2004, 28, 497-505.

(10.) Festing, S., Wilkinson, R., The ethics of animal research. Talking Point on the use of animals in scientific research. EMBO Rep 2007 Jun; 8(6): 526-530.

(11.) Cristofor, A. C., Mititelu-Tartau, L., Popa, G. et al., The influence of some antidepressant drugs on spatial memory in rats. Farmacia 2015, 63(4): 526-529.

(12.) Mititelu-Tartau, L., Popa, G. E., Rusu, G. et al., Bupropion, but not fluvoxamine improves spatial memory acquisition in old rats. Eur Neuropsychopharmacol 2015, P.1.g.004, 25(2), S240.

(13.) Popa, E. G., Cristofor, A. C., Lupusoru, C. E. et al., Experimental investigation on the effects of some antidepressants on spatial memory performance of old rats. Eur Neuropsychopharmacol 2015, P.2.a.002, 25(2), S375-S376.

(14.) Yuce, M., Ilkaya, F., Karabekiroglu, K. et al., Improving effect of atomoxetine and reboxetine on memory in passive avoidance task. Bulletin of Clinical Psychopharmacology 2014; 24(3): 211-9.

(15.) De Bundel, D., Femenia, T., DuPont, C.M. et al., Hippocampal and prefrontal dopamine D1/5 receptor involvement in the memory-enhancing effect of reboxetine. Int J Neuropsychopharmacol 2013, 16(9):2041-51.

(16.) Warner, T. A., Drugan, R. C., Morris water maze performance deficit produced by intermittent swim stress is partially mediated by norepinephrine. Pharmacol Biochem Behav 2012; 101(1):24-34.

(17.) Hughes, R., Gray, V., Drug-, dose- and sex-dependent effects of chronic fluoxetine, reboxetine and venlafaxine on open-field behavior and spatial memory in rats. Behav Brain Res 2015, Vol. 281, 43-54.

Ana C. CRISTOFOR--M. D., Ph. D. Student, Department of Pharmacology--Algesiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Romania

Roxana CHIRITA--Professor, M. D., Ph. D., Department of Psychiatry, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Liliana MITITELU-TARTAU--Lecturer, M. D., Ph. D., Department of Pharmacology--Algesiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Gabriela RUSU--Teaching Assistant, M. D., Ph. D. Student, Department of Pharmacology--Algesiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Gratiela E. POPA--Professor Assistant, M. D., Ph. D., Department of Pharmaceutical Technology, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Raoul V. LUPUSORU--Lecturer, M. D., Ph. D., Department of Pathophysiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Catalina E. LUPUSORU--Professor, M. D., Ph. D., Department of Pharmacology--Algesiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Correspondence:

Liliana MITITELU-TARTAU

No. 16 Universitatii Street, zip code 700115, Iasi, Romania

E-mail: lylytartau@yahoo.com

Tel.: + 40 744 606 020

Submission: January, 04th, 2015

Acceptance: February, 11th, 2015
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Article Details
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Author:Cristofor, Ana C.; Chirita, Roxana; Mititelu-Tartau, Liliana; Rusu, Gabriela; Popa, Gratiela; Lupuso
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Mar 1, 2016
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