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The effects of magnesium antidepressants co-administration on the spontaneous behaviour in old rats.

BACKGROUND

Depression has been described since ancient times by Hippocrates, who hypothesized that the etiology of this affective disorder involved various humoral disturbances in the body, and also described its main clinical manifestations. Over time, it has been revealed that under depressing conditions, significant changes in affective behaviour and mood occur with the predominance of a state of sadness, deep suffering, and a slowing of psychomotor activity. The manifestations of the disease may be mild, moderate or severe, can be recognized by the affected person or may be observed by the entourage (1). Nowadays, life expectancy is steadily rising, around 10% of the general population being over 65 years of age; this is reflected in the increasing of the neurodegenerative diseases and the affective disorders incidence (2). This stage of life is linked with important changes in the way the person perceives himself and the world around him, which are manifested on all levels: biological (physical regression, disruption of physiological processes, fragility of the body), family, professional, economic and social (3).

Depression in the elderly does not significantly differ from the depression at younger age, but in many cases, addressability to the doctor is late and most often followed by the extreme gesture, suicide (4).

Frequently, as in all types of affective disorders, depression in elderly is often under-diagnosed and insufficiently treated, statistical data highlighting that the majority of older persons (over 70%) who have attempted suicide, had previously requested a medical investigation (5).

The treatment of geriatric depression is usually complex, frequently combining pharmacologic methods with nonpharmacological procedures, such as: psychotherapy, hypnosis, physical therapies. Selective serotonin reuptake inhibitors and both serotonin-norepinephrine reuptake inhibitors are preferred instead of tricyclic antidepressants, due to their good tolerability, cardiovascular safety, low anticholinergic activity (6) (7).

Magnesium is one of the most wide-spread bivalent cation in the environment, being the fourth major element in the organism (after sodium, potassium and chloride), and the second most abundant within the cells (8). It plays a key role in the body homeostasis, being involved as enzyme cofactor in more than 300 biochemical processes. It has also an essential factor in the energy production, oxygen uptake, central nervous system function, electrolyte balance, glucose metabolism and muscle activity (9) (10).

Moreover, various experimental researches and clinical trials have revealed the beneficial effect of magnesium supplementation in the clinical symptomatology and the therapeutic response to classical antidepressant drugs, in patients with affective disorders (11).

WORKING HYPOTHESIS

Because many of the antidepressants are currently reported in the treatment scheme for elderly patients with affective disorders, we have considered useful to investigate the influence of some antidepressants with different mechanisms of action, alone or in combination with magnesium, exerted on old laboratory animals, on a standardized behavioural model. Investigating how these antidepressants interfere with spontaneous behaviour and motor activity could result in new data regarding the pathophysiological mechanisms of affective disorders and provide useful information on the efficacy of these drugs in the treatment of various affective disorders in the elderly.

The purpose of our study was to evaluate the effects of magnesium associated with sertraline and venlafaxine on the spontaneous behavior and the motor activity in old rats.

MATERIAL AND METHOD

Wistar male old rats (aged 18 months) were used in the experiment. The animals were housed in plastic cages, under standard laboratory environment (a 12-hour dark cycle with light period between: 07:00-19:00), a constant temperature of 23 [+ or -] 1[degrees]C and relative air humidity 5565%), were fed with standard pellets, and had free acces to water.

The rats were randomly separated into 6 groups of 7 animals each, treated orally, during 1 month, according to the following protocol:

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

Group II (Mg): magnesium chloride 1 mmol//kbw;

Group III (SRT): sertraline 3 mg/kbw;

Group IV (VLX): venlafaxine 8 mg/kbw;

Group V (SRT+Mg): sertraline 3 mg/kbw + magnesium chloride 1 mmol//kbw;

Group VI (VLX+Mg): venlafaxine 8 mg/kbw + magnesium chloride 1 mmol//kbw.

The drugs: sertraline and venlafaxine (purchased from Sigma-Aldrich Chemical Company)--were extemporaneously dissolved in 0.9% saline solution. To avoid the chronobiology interferences, the experiments were performed during the same time interval (between 8:00 a.m. to 2:00 p.m.).

To evaluate the effects of these two antidepressants on the spontaneous behaviour, the present study estimated the influence of sertraline and venlafaxine on the rat exploratory behaviour and the motor activity on the Actimeter Panlab Apparatus. This device consists of three transparent plastic chambers, equipped with two infrared sources. The system is fully modular, allowing simultaneous recording of the horizontal, vertical and stereotype movements, during an investigation session of 20 minutes. Horizontal or vertical movements, as well as stereotypical activity are counted based on the number of infrared beam interruptions and are automatically recorded by the data processing software (12).

Over the allocated period within this experimental behavioural model, it is considered that: the decrease in the number of total movements, compared to the control group, corresponds to an anxiolytic or sedative effect in the laboratory animal (13), while the intensification of total motor activity is correlated with an anxious behaviour, in which the vertical movements correspond to the escape attempts of the animal placed in an unknown environment (14).

The data were expressed as mean +/standard deviation, and the significance was assessed using the SPSS Program for Windows version 17.0, the ANOVA oneway method and the Newman-Keuls posthoc test. The values of p below 0.05 were considered to be significant compared to control group. The study protocol was reviewed and approved by the Ethics Committee on Research of the 'Grigore T. Popa' University of Medicine and Pharmacy, Iasi, Romania, in agreement with the international ethical regulations regarding the care and handling of laboratory animals (15).

RESULTS AND DISCUSSIONS

The evaluation of the spontaneous motor activity in experimental animals represents a valuable method for the assessing the central neurobehavioral effects of the tested substances (12) (14).

Chronic treatment with Mg (1 mmol / kg body weight) was accompanied by a decrease of the number of movements in the horizontal plane (1936.71 [+ or -] 56.53), of the escape attempts (254.57 [+ or -] 55.02) and also of the self-maintenance spontaneous behaviour (843.86 [+ or -] 79.69), statistically significant (** p<0.01) compared to the control group in the Actimeter test in old rats.

This diminution of the global spontaneous motor activity could be generally assimilated with an anxiolytic-like action in humans.

The oral administration, during one month, of SRT and VLX resulted in a significant (** p<0.01) decrease of the space exploration capacity (2014.14 [+ or -] 236.62, respectively 1614.14 [+ or -] 93.13) and also of the vertical movements number (252.29 [+ or -] 62.15, respectively 241.29 [+ or -] 19.57). VLX (973.57 [+ or -] 53.05), but not SRT, induced an important diminution of the animal stereotype activities (* p<0.05). The effects of VLX were more intense than those of SRT in this behavioural model in old rats.

The use of SRT+Mg and VLX+Mg were linked by a substantial (**p<0.01) reduction of the number of both horizontal (1823.29 [+ or -] 105.17, respectively, 1473.71 [+ or -] 208.43) and vertical (245.29 [+ or -] 54.91, respectively 227.86 [+ or -] 26.60) movements in the same time interval of determination. VLX+Mg (812.71 [+ or -] 74.90), but not SRT+MG produced a notable diminution of the old rats stereotype activities in the Actimeter test (** p<0.01).

Co-administration of Mg and the investigated antidepressants emphasized further reduction of the general spontaneous behaviour, these modifications being correlated, to some extent, with the sedative effects manifested in humans.

Reports in the literature have demonstrated that the pathological mechanisms involved in the development of affective disorders are mediated by numerous neurotransmitters, such as norepinephrine, serotonin, dopamine, acetylcholine, gamma-aminobutyric acid, glutamate (16).

To explain the phenomena accountable for the occurrence of depression, several theories were issued related to the neurotransmitters involved in the pathways responsible for the affective disturbances (17). It has been postulated that depressive manifestations are caused by the lack of one or more of three key neurotransmitters (serotonin, dopamine, norepinephrine) in the synapses of the central nervous system. Experimental researches performed on laboratory animals have shown that substances which enhance the synaptic levels of serotonin and norepinephrine exhibit relevant antidepressant effects (18) (19) (20).

The decrease of these mediators concentration in the brain is responsible for the clinical manifestations that accompany depression, and the patient response to the antidepressant therapy varied depending on the predominant action of each class of the agents on one or more of the neurotransmitters involved in the pathological mechanisms of affective disorders (20).

CONCLUSIONS

Using a classic behavioural model, the Actimeter test, we have demonstrated that the chronic use of antidepressants: sertraline and venlafaxine induces the decreasing of the motor activity and spontaneous behaviour in old rats.

The combination of magnesium chloride to the studied antidepressant drugs (sertraline and venlafaxine) enhances the decreasing of the exploratory capacity and spontaneous activity in this behavioural model in old rats.

Our obtained data are suggestive, but we consider that is difficult to extrapolate these results to humans, due to the huge structural and psycho-behavioural differences between laboratory animal and the patient.

Correspondence:

Liliana Mititelu-TARTAU No. 16 Universitatii Street, postal code: 700115 Telephone: 0744606020 E-mail: lylytartau@yahoo.com

Submission: 14 July 2017

Acceptance: 01 August2017

AKNOLEDGEMENT AND DISCLOSURE

The authors have no potential conflict of interests to disclose

REFERENCES

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(8.) Maguire, M.E., Cowan, J.A. Magnesium chemistry and biochemistry. Biometals 2002; 15: 203-210.

(9.) Jahnen-Dechent, W., Ketteler, M., Magnesium basics. Clin Kidney J 2012, 5, Suppl 1: i3-i14.

(10.) Romani, AM.P, Chapter 4 Magnesium Homeostasis in Mammalian Cells. In Banci, Lucia (Ed.). Metallomics and the Cell. Metal Ions in Life Sciences. 12. Springer, 2013.

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(19.) Dayan, P., Huys, Q.J.M. Serotonin in affective control. Annu Rev Neurosci 2009, 32: 95-126.

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Ana C. Cristofor--Assistant, MD., PhD, Department of Psychiatry, "Grigore T. Popa" University of Medicine and Pharmacy Ia?i, Psychiatry "Socola" Institute of Psychiatry Ia?i, Romania

Liliana Mititelu-TARTAU--Assoc. Prof., MD, PhD, Department of Pharmacology-Algesiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Magdalena Birsan, Assistant, Pharm. PhD, Department of Pharmaceutical Technology, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Raoul V. Lupusoru--Assoc. Prof., MD, PhD, Department of Pathophysiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Roxana Chirita--Prof, MD., PhD, Department of Psychiatry, "Grigore T. Popa" University of Medicine and Pharmacy Iasi, Psychiatry "Socola" Institute of Psychiatry Ia?i, Romania

Catalina E. Lupusoru--Prof., MD, PhD, Department of Pharmacology-Algesiology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania

Caption: Figure no. 1. Effects of sertraline and venlafaxine administration on the horizontal movements number in the Actimeter test. The values are expressed as mean [+ or -] SD of the horizontal movements number for 7 animals. ** p<0.01 vs. control.

Caption: Figure no. 2. Effects of sertraline and venlafaxine administration on the vertical movements number in the Actimeter test. The values are expressed as mean [+ or -] SD of the vertical movements number for 7 animals. ** p<0.01 vs. control.

Caption: Figure no. 3. Effects of sertraline and venlafaxine administration on the stereotype movements number in the Actimeter test. The values are expressed as mean [+ or -] SD of the stereotype movements number for 7 animals. * p<0.05, ** p<0.01 vs. control.
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Author:Cristofor, Ana C.; Mititelu-Tartau, Liliana; Birsan, Magdalena; Lupusoru, Raoul V.; Chirita, Roxana;
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Sep 1, 2017
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