The influence of aripiprazole and venlafaxine on the antidepressant-like effect observed in prenatally stressed rats (animal model of depression)

Abstract

Depression is a nosological entity which may appear alone or concomitantly (e.g. in schizophrenia). Analysis of data from both clinical and experimental studies allows a conclusion that atypical antipsychotics, such as aripiprazole (ARI), may also be effective in treating depression in addition to antidepressants. The aim of the studies was to determine antidepressant efficacy of ARI, venlafaxine (VEN) and combined therapy using both drugs, in prenatally stressed rats (animal depression model) and control group. In addition, this article was aimed at determining the effect of these drugs on locomotor activity of these animals. The effect of chronic stress used in pregnant rats and the use of drugs such as ARI (1.5 mg/kg) and VEN (20 mg/kg) were studied in forced swimming test (FST; antidepressant effect) and locomotor activity test. Performed tests confirmed the antidepressant effect of ARI, VEN and efficacy of combined drugs in FST in both prenatally stressed rats (effect present upon single administration and after 7, 14 and 21 days of testing) and control group rats (effect present upon single administration and 7 days of testing). Moreover, upon single administration of the used drugs to prenatally stressed rats, it was found sedative effect – reduced animals’ locomotor activity. Study results have proven antidepressant and sedative efficacy of ARI, VEN and combined administration of these drugs. Due to the small amount of data on the above preparations, in particular in the context of animal depression models, further studies in this respect are recommended.

Keywords

Animal model of depression aripiprazole venlafaxine immobility time locomotor activity

Introduction

Depression is one of the most common mental disorders observed in the global population.¹ The disease affects young and older people alike. Severe depressive disorders affect at least 3% of the global population, and in the European countries, the incidence rate is as high as 4–9%. Epidemiological data show an increased incidence over the recent years.² According to WHO, in 2002 depression was the fourth most common cause of disability. Analyses show that in 2030 depression will be the second most common disabling disease in developed countries (third in less-developed countries).³

As far as treatment of depression is concerned, the experts agree that pharmacotherapy remains the primary treatment method. According to clinical data,⁴ only 20% of patients are covered by medical care, and depression is correctly diagnosed only in 30–50% of the patients.⁵ In addition to this, as many as 30–40% of patients fail to respond or respond insufficiently to the first-line pharmacotherapy applied. Suicides are also a major problem in depressive disorders. It is estimated that as many as 25% of patients with severe depression (requiring hospital treatment) have a high risk of suicide.⁵ Other data show that as many as 70% of all suicide attempts are made by people suffering from depression.⁵ These disorders are also characterized by relapses of disease episodes. Of patients after one depressive episode, 50% experience a relapse of the disorders. This rate increases in patients who had more than one depressive episode – 80% after two episodes and up to 90% after three episodes.⁵

Depressive disorders present also in other mental diseases, such as schizophrenia. High rates of comorbidity of depression and schizophrenia correlate with high unemployment rate, low earnings, poor physical health and frequent abuse of alcohol and other intoxicants among the patients. The problem with disease diagnosis consists in similarity of schizophrenia’s negative symptoms with depressive disorders’ symptoms.⁶ References concerning depression’s prevalence in patients suffering from schizophrenia vary highly from 6% to 75%.^7
–9 This variation is primarily due to the definition of depression adopted in individual studies, analysis of the patient’s behaviours and duration of the patient’s observation. It can be undoubtedly said that approximately 25% of schizophrenic patients additionally suffer from depression which is why research on combined administration of antidepressants and antipsychotics to treat both severe depressive disorders and comorbid schizophrenia and depression seems to be so important.⁶

Animal depression models definitely can be used in medical sciences to better understand the aspects related to origin and methods of treatment of this disease.¹⁰ The present study uses animal prenatal stress model¹¹ consisting in induction of chronic stress in key periods of prenatal foetal brain development resulting in behavioural changes later in their life. For rats, the period from day 14 to day 21 of pregnancy is critical for development of their nervous system; thus, exposure of foetuses in this period to stress, as well as toxins or hypoxia (depending on the model), severely disturbs the neurogenesis process.¹¹

Aripiprazole (ARI) is an atypical neuroleptic, affecting D₂ receptor both as a partial agonist in mesocortical structures and an antagonist in the mesolimbic route. In addition to this, ARI is a strong antagonist of 5-HT_2A receptors and a partial agonist of the 5-HT_1A receptor.¹² ARI’s antipsychotic properties are most probably related to combined antagonistic effect on D₂ receptors located in the mesolimbic system (mitigation of positive symptoms) and antagonism to 5-HT_2A receptors in the frontal cortex (reduction in negative symptoms).¹³ ARI additionally has a strong affinity to the D₃ receptor and moderate affinity to D₄, 5-HT_2C and 5-HT₇ receptors,¹⁴ has no anticholinergic effect and has low antagonistic effect to H₁ and α₁ receptors.¹⁴ Antagonism to H₁ receptors may explain the drowsiness observed upon administration of this drug, while antagonism to α₁ receptors may explain the presence of orthostatic hypotension.¹⁴ ARI is used to treat schizophrenia, moderate-to-severe manic episodes and bipolar affective disorders and to prevent new manic episodes.

Venlafaxine (VEN) is an antidepressant from the group of serotonin and noradrenaline reuptake inhibitors (SNRIs).¹⁵ The mechanism of antidepressant effect is related to enhanced neurotransmitter activity within the central nervous system. Both VEN and its active metabolite (O-desmethylvenlafaxine) are serotonin and adrenaline reuptake inhibitors. VEN is also a dopamine reuptake inhibitor.¹⁵ Neither the main substance nor its metabolite has any effect on muscarinic, histaminic or α-1-adrenergic receptors.¹⁵ VEN is used to treat and prevent relapses of severe depression and treat generalized anxiety disorders, social phobias and panic disorder without accompanying agoraphobia.¹³

This article analyses the antidepressant effect of ARI (antipsychotic drug), VEN (antidepressant drug) and combined administration of both drugs in control rats and prenatally stressed rats (animal depression model). The article is also aimed at determining the effect of these drugs on locomotor activity of the animals

Methods

Animal

Timed pregnant Wistar female rats (30) were purchased from Poznan University of Medical Sciences, Poznan, Poland (licensed by the Ministry of Agriculture in Warsaw, Poland), and arrived at our animal facility on day 2 of gestation. The pregnant animals were housed individually in cages (size 42 cm × 26 cm) in a light- (lights on 07.00–19.00 h), temperature- and humidity-controlled animal facility. The dams had free access to rat chow (Labofeed B) and water.

For behavioural tests, male rats born to mothers exposed to prenatal stress and non-stressed control group during pregnancy were used. Male rats were housed in cages (size 54 cm × 32 cm).

The total number of animals in the study was 126 (30 females, 96 males). The male rats were the offspring of either 15 prenatally stressed females (delivered 48 prenatally stressed male rats animal depression group (ADG)) or 15 non-stressed females (delivered 48 control group rats animal non-depression group (ANG)). Animals were divided according to the following schedule:

Porsolt test (48 male rats)

ANG (24 rats)

Saline (6 rats)

ARI (6 rats)

VEN (6 rats)

ARI + VEN (6 rats)

ADG (24 rats)

Saline (6 rats)

ARI (6 rats)

VEN (6 rats)

ARI + VEN (6 rats)

Locomotor activity test (48 male rats)

ANG (24 rats)

Saline (6 rats)

ARI (6 rats)

VEN (6 rats)

ARI + VEN (6 rats)

ADG (24 rats)

Saline (6 rats)

ARI (6 rats)

VEN (6 rats)

ARI + VEN (6 rats)

All procedures related to the use of rats in these experiments were conducted with due respect to ethical principles regarding experiments on animals (Directive 2010/63/EU). The study protocol was approved by the Local Ethical Commission for Research on Animals in Poznan.

Drugs

Drugs used in the experiments are as follows:

ARI – Abilify, Otsuka Pharmaceutical Europe, Bristol-Myers Squibb Poland;

VEN – Velafax, Farmacom Sp. z o.o., Poland;

The rats were administered with ARI (1.5 mg/kg ip), VEN (20 mg/kg po) or the vehicle (saline ip) 30 min before the test for ARI and 60 min before the test for VEN in chronic treatment (21 days). ARI and VEN were suspended in saline (1% carboxymethylcellulose vehicle dissolved in sodium chloride NaCl in the 1:1 ratio). The saline was given to control group according to the same schedule. Different groups of animals were used for different tests.

Animal model of depression

Pregnancy was determined by observation of vaginal plugs (embryonic day 0 – E0).¹¹ Restraint stress was performed daily during the last week of pregnancy (E14–E21). Pregnant female rats were individually restrained three times a day (at approximately 9:00 a.m., 1:00 p.m. and 5:00 p.m.) for 45 min in transparent metal cylinders while at the same time being exposed to bright light. Control pregnant females were left undisturbed in their home cages.

Forced swimming test

We used the Porsolt forced swimming test (FST)¹⁶ to measure immobility time (IT):

Pretest: Twenty-four hours prior to the experiments, the rats were individually placed in plexiglass cylinders (height 40 cm, diameter 18 cm) containing water (25°C) up to 17 cm of the cylinder’s height. Fifteen minutes later, the rats were removed to a 30°C drying room for 30 min.

Test: ARI (1.5 mg/kg) and VEN (20 mg/kg) were administered 24 h after the pretest. Thirty minutes after drug administration, the rats were placed in the cylinders and immobility was measured for 5 min. A rat was judged to be immobile when it remained floating in the water in an upright position and only made very small movements necessary to keep its head above water. The total duration of immobility over the 5-min period was recorded by an observer unaware of the treatment applied to the rats.

We also examined drug effects after prolonged administration (7, 14 and 21 days).

The water was changed after the observation of each rat.

Locomotor activity

Locomotor activity was measured in rats (ANG and ADG) using eight 20.5 cm × 28 cm × 21 cm wire grid cages, each with two horizontal infrared photocell beams along the long axis, 3 cm above the floor. Photocell interruptions were recorded by electromechanical counters in an adjacent room. Before the test, all groups of animals were habituated to a novel cage within 30 min. Rats were also treated with 1.5 mg/kg ARI (ip), 20 mg/kg VEN (po) or saline. Then, photocell activity would be recorded at 5-min intervals. This test provided an index of basal locomotor activity of animals in a familiar environment, necessary to indicate the presence of a central stimulant or sedating effects of the drug used in the test.

Statistical analysis

The data are shown as the mean values ± SEM. The data distribution pattern was not normal (unlike Gaussian function). Statistical analyses for the FST and locomotor activity test were carried out using the non-parametric Kruskal–Wallis H test for unpaired data and Friedman two-way analysis of variance (ANOVA) test for paired data. Statistical significance was tested using Dunn’s and Dunnet’s post hoc test.

Ethical approval

All applicable international, national and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Results

1. Effect of single and chronic treatment of ARI, VEN and combined administration of these drugs on IT analysed in the FST on rats with experimentally induced animal model of depression (prenatal stress).

Single and repeated administration (7 days) of ARI at the dose of 1.5 mg/kg of body weight (ip) 30 min prior to the test resulted in a statistically significant reduction in the IT of animals in the ANG compared to the control group (p < 0.05 vs. ANG CONTROL; Table 1). Single and repeated administration (7 days) of VEN at the dose of 20 mg/kg of body weight (po) 60 min prior to the test, meanwhile, resulted in a statistically significant reduction in the IT of ANG animals compared to the control group, like after administration of ARI (p < 0.05 vs. ANG CONTROL; Table 1). Similar results, a statistically significant reduction in the IT of ANG animals compared to the control group (p < 0.05 vs. ANG CONTROL; Table 1) were obtained upon single and repeated (7 days) combined administration of ARI + VEN (administered 30 and 60 min prior to the test at the doses of 1.5 and 20 mg/kg, respectively).

Table 1.

Effect of single and chronic treatment of ARI, VEN and combined administration of these drugs on IT analysed in the FST on rats with experimentally induced animal model of depression (prenatal stress).^a

Group	IT (s)				Friedman^3,17
	Single administration (x ± SEM)	Chronic treatment
	Single administration (x ± SEM)	7 days (x ± SEM)	14 days (x ± SEM)	21 days (x ± SEM)
ANG
CONTROL	241.16 ± 2.04	267.50 ± 5.48^b	269.00 ± 5.62^b	275.83 ± 3.9^b	4.7
ARI 1.5 mg/kg ip 30 min before the test	216.66 ± 4.73^e	233.16 ± 10.72^e	268.16 ± 6.46^bc	274.00 ± 4.87^bc	4.4
VEN 20 mg/kg po 60 min before the test	200.33 ± 7.98^e	225.66 ± 9.79^be	265.83 ± 3.35^b	273.00 ± 3.99^b	6.8
ARI 1.5 mg/kg ip VEN 20 mg/kg po 30/60 min before the test	205.33 ± 5.09^e	236.50 ± 8.05^be	261.00 ± 3.32^bc	268.66 ± 3.33^bc	5.7
ADG
CONTROL	274.50 ± 2.52^e	279.16 ± 4.91	279.00 ± 3.75	272.16 ± 2.67	2.7
ARI 1.5 mg/kg ip 30 min before the test	244.00 ± 13.45^f	255.66 ± 8.62^f	261.00 ± 5.22^f	260.16 ± 3.81^f	2.8
VEN 20 mg/kg po 60 min before the test	230.33 ± 8.48^f	253.33 ± 7.08^bf	260.66 ± 4.99^bf	256.50 ± 4.47^bf	4.6
ARI 1.5 mg/kg ip VEN 20 mg/kg po 30/60 min before the test	244.50 ± 4.26^f	255.33 ± 9.00^f	256.33 ± 7.25^f	254.66 ± 6.78^f	2.3
Kruskall–Wallis^7,47	10.5	6.5	4.4	4.8

ARI: aripiprazole; VEN: venlafaxine; IT: immobility time; FST: forced swimming test; ANG: animal non-depression group; ADG: animal depression group.

^aNumber of housed animals = 6.

^bStatistically significant difference p < 0.05 versus single treatments.

^cStatistically significant difference p < 0.05 versus 7 days of treatments.

^dStatistically significant difference p < 0.05 versus 14 days of treatments (non-significant in all groups).

^eStatistically significant difference p < 0.05 versus ANG CONTROL.

^fStatistically significant difference p < 0.05 versus ADG CONTROL.

As shown in Table 1, there was a statistically significant increase in the IT of animal non-depression control group at day 7, 14 and 21 of the experiment as compared to day 1 of FST (p < 0.05 vs. 1 day). Moreover, after prolonged administration (14–21 days) of ARI (1.5 mg/kg) in ANG, a statistically significant increase in the IT as compared to single (p < 0.05 vs. single treatment) and chronic 7 days’ treatment (p < 0.05 vs. 7 days) was observed. Chronic administration (7–21 days) of VEN (20 mg/kg), meanwhile, produced a statistically significant increase in the IT only in comparison with single treatment (p < 0.05 vs. single treatment). In addition to this, a statistically significant increase in the IT was observed after concomitant and prolonged (7–21 days) administration of ARI + VEN as compared to single treatment (p < 0.05 vs. single treatment) and after concomitant and prolonged (14–21 days) administration of drugs as compared to chronic 7 days’ treatment (p < 0.05 vs. 7 days).

In ADG, single and repeated administration (7, 14 and 21 days) of ARI at the dose of 1.5 mg/kg of body weight 30 min prior to the test resulted in a statistically significant reduction in the IT of animals compared to the control group (p < 0.05 vs. ANG CONTROL; Table 1). Similar results were obtained upon VEN administration at the dose of 20 mg/kg of body weight (po) 60 min prior to the test – single and repeated administration (7, 14 and 21 days) resulted in a statistically significant reduction in the IT of ADG animals compared to the control group (p < 0.05 vs. ADG CONTROL; Table 1). Combined administration of ARI and VEN (administered 30 and 60 min prior to the test at the doses of 1.5 and 20 mg/kg, respectively) yielded a statistically significant reduction in the IT (single and repeated administration for 7, 14 and 21 days) of ADG animals compared to the control group (Table 1).

Furthermore, in ADG, a statistically significant increase in the IT was observed after prolonged administration (7–21 days) of VEN (20 mg/kg) in comparison with single VEN treatment (p < 0.05 vs. single VEN treatment; Table 1). No statistically significant changes were observed in the IT after ARI and ARI + VEN concomitant administration as well as in control group in terms of therapy durations.

Comparison of control groups shows a statistically significantly higher IT of ADG animals compared to the ANG (p < 0.05 vs. ANG CONTROL) observed on day 1 of the test. This result is the evidence of correctly applied animal depression model in which animals from the prenatally stressed group show a longer IT compared to non-prenatally stressed rats (Table 1).

2. Effect of single administration of ARI, VEN and combined administration of these drugs on locomotor activity of rats with induced animal model of depression (prenatal stress).

Single administration of ARI (at the dose of 1.5 mg/kg of body weight, 30 min prior to the test), VEN (at the dose of 20 mg/kg of body weight, 60 min prior to the test) and ARI + VEN (administered 30 and 60 min prior to the test at the doses of 1.5 and 20 mg/kg of body weight, respectively) failed to yield a statistically significant change in the mobility of animals in the ANG compared to the control group (p < 0.05 vs. ANG CONTROL; Table 2).

Table 2.

Effect of single administration of ARI, VEN and combined administration of these drugs on locomotor activity of rats with induced animal model of depression (prenatal stress).^a

Group	Locomotor activity/activity count
Group	Single treatment (x ± SEM)
ANG
CONTROL	54.16 ± 3.28
ARI 1.5 mg/kg ip 30 min before the test	50.66 ± 3.47
VEN 20 mg/kg po 60 min before the test	49.83 ± 4.07
ARI 1.5 mg/kg ip VEN 20 mg/kg po 30/60 min before the test	44.80 ± 3.24
Animal depression group (ADG)
CONTROL	117.33 ± 4.17^b
ARI 1.5 mg/kg ip 30 min before the test	89.00 ± 6.51^c
VEN 20 mg/kg po 60 min before the test	88.60 ± 2.97^c
ARI 1.5 mg/kg ip VEN 20 mg/kg po 30/60 min before the test	59.16 ± 3.90^c
Kruskall–Wallis^7,18	17.7

ARI: aripiprazole; VEN: venlafaxine; ANG: animal non-depression group.

^aNumber of housed animals = 6.

^bStatistically significant difference p < 0.05 versus ANG CONTROL.

^cStatistically significant difference p < 0.05 versus ADG CONTROL.

In ADG, on the other hand, single administration of ARI (at the dose of 1.5 mg/kg of body weight, 30 min prior to the test), VEN (at the dose of 20 mg/kg of body weight, 60 min prior to the test) and ARI + VEN (administered 30 and 60 min prior to the test at the doses of 1.5 and 20 mg/kg of body weight, respectively) resulted in a statistically significant reduction in the animal mobility compared to the control group (p < 0.05 vs. ADG CONTROL; Table 1).

Comparison of control groups shows a statistically significantly higher locomotor activity observed in ADG animals compared to the ANG (p < 0.05 vs. ANG CONTROL). This result is the evidence of a correctly applied animal depression model (Table 1).

Discussion

In conducted tests, both single and repeated administration (7 days) of ARI in the ANG (non-stressed) have shown an antidepressant effect (reduced IT) observed in the Porsolt test.¹⁶ Lack of effect upon further administrations of the drug (after 14 and 21 days) may be due to the development of a tolerance to the antidepressant effect. This phenomenon consists in the declining effect of the drug used developing over time, resulting in higher dosage required to achieve the same effect which is an adverse consequence of the therapy applied. Similar results were also obtained in our previous studies for ARI at the dose of 1.5¹⁹ and 6 mg/kg.²⁰ ARI’s antidepressant effect may be associated with its ability to increase dopamine levels in mesocortical structures, where it acts as a partial agonist, and its efficacy depends on the drug dose administered.¹⁹ It should also be mentioned that ARI’s partial agonism of D₂ receptors in combination with antagonism of 5-HT_2A receptors minimizes the risk of dopamine insufficiency in the nigrostriatal and tuberoinfundibular pathways, but also the risk of drug-induced Parkinsonism or hyperprolactinaemia.²¹ Literature data indicate that ARI also induce the increase in DA levels in the occipital cortex and in the cerebellum,²² which explains their effect on 5-HT_1A receptors. On the other hand, blocking 5-HT₂ serotonin receptors is with effect on other neurotransmission systems (multireceptor mechanism of ARI) is believed to be responsible for the antideficit, antidepressant and procognitive effect of drug.²³ Results of clinical trials also lead to a conclusion that atypical antipsychotics may be effective in supplementary treatment of resistant and severe depressive episodes.²⁴ Study by Berman et al.¹⁷ confirm the efficacy of ARI as a drug supplementing treatment of severe depressive disorders with drugs such as ecitalopram, fluoxetine, controlled-release paroxetine, sertraline and prolonged-release VEN. In their studies, Berman et al.²⁵ have also shown that combined administration of the analysed antidepressants with ARI was safe for the patients.

Results of VEN administration in the ANG show that both single and repeated administration (7 days) of this drug resulted in a reduced IT (antidepressant effect) observed in the Porsolt test. Similar results in several independent studies were obtained by Nowakowska et al.^26
–28 Study by Redrobe et al.²⁹ has also proven reduced IT upon single VEN administration at the doses of 8, 16, 32 and 64 mg/kg of body weight. In these studies, the authors have also confirmed that VEN at low doses inhibits serotonin reuptake and at higher doses inhibits serotonin and noradrenalin reuptake. Also, other researchers observed VEN’s antidepressant effect upon single administration to animals.^30

–34 The observed effect of VEN (reduced animal IT observed in the Porsolt test) is probably related to the effect of this drug on 5-HT₁, 5-HT₂ and 5-HT₃ receptors.^29,35 VEN as well as ARI also generate the increase in the total dopamine (DA) level and simultaneously decrease in DA metabolites level 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat’s hippocampus upon the administration of 20 mg/kg VEN.³⁶ Moreover, observation suggests also that the potentialization of VEN’s procognitive effect may be related to increase in serotonin (5-HT) and decrease in their metabolite levels (5-HIAA) in the same area of the brain – hippocampus. Having in mind that only very large doses of VEN lead to DA reuptake inhibition, it may be assumed that the observed DA level increase is related to another mechanism than neurotransmitter’s reuptake inhibition.³⁶

In the case of combined ARI and VEN administration in the ANG, antidepressant effect in the Porsolt test would still be observed which may be related to the increased neurotransmitter (mainly dopamine and serotonin) levels in the striatum. Increased dopamine level in mesocortical structures (responsible for motivation), in turn, may cause a reduced IT observed in the Porsolt test. ARI may also affect the nucleus accumben which participates in regulation of dopaminergic activity by controlling impulsive and emotional functions. Increased amounts of serotonin and noradrenalin in the brain stem, related to the mechanism of action of the study drugs, may in turn be responsible for increased motor activity of animals. Studies on efficacy and safety of combined administration of VEN and ARI to treat drug-resistant and severe depressive disorders show that such a therapy is well tolerated by the patient.³⁷ Study on ARI’s effect on pharmacokinetics of antidepressants, that is, ecitalopram, fluoxetine and paroxetine, has shown no changes in their basic pharmacokinetic parameters.³⁸ This study has also confirmed a good safety profile of these drugs in combined administration.³⁸ It is worth to mention that combined use of ARI and VEN may cause side effects like dizziness, drowsiness, confusion and difficulties related to concentration. These problems are associated with depressant effect on central nervous system of used drugs.

Tests conducted on the prenatally stressed ADG show that both single and repeated administration of ARI resulted in the antidepressant effect observed in the animals in the Porsolt test which corroborates with the previously obtained results for the animal schizophrenia model.¹⁹ ARI’s antidepressant effect has also been confirmed in the study by Russo et al.³⁹ in a genetic model of animal absence seizures with accompanying mild depression. Results obtained by Burda-Malarz et al. in the Porsolt test⁴⁰ were different but the study used a higher dose of ARI (6 mg/kg). ARI’s antidepressant effect in the conducted study results from its ability to stabilize the dopaminergic and serotoninergic system. As a partial agonist of D₂, 5-HT1A and 5-HT_2C receptors and antagonist of D₂ and 5-HT_2A receptors, ARI may inhibit or stimulate body functions depending on the patient’s condition. Antidepressant effect is based on the drug’s ability to stabilize the dopaminergic system and on its effect on the 5-HT_1A receptor.⁴¹ This makes this drug fit for use not only in antipsychotic therapy but also in treating depression.¹⁹

The study also found that VEN has an antidepressant effect both upon single and repeated administration in the ADG of prenatally stressed rats. Similar outcome was achieved also by Nowakowska et al.²⁸ in animals with induced estrogen level variation (ovariectomy). Dhir et al.,⁴² likewise, in their mice model of chronic fatigue, observed a reduced animal IT upon single and repeated administration of VEN and reversal of adverse biochemical parameters and neurotransmitter levels in animals as a result of pharmacotherapy used. Abdel-Wahaba et al.,⁴³ on the other hand, confirmed VEN’s antidepressant effect and, in addition to this, its ability to protect the body against oxidation stress in mice with damaged DNA. VEN’s antidepressant effect both upon single and repeated administration was also observed in the Porsolt test by Martisov et al.⁴⁴ in another animal depression model (offspring separation from the mothers). This study found that upon chronic administration of VEN effects induced by early stress (reduced corticosterone level and increased gamma-Aminobutyric acid (GABA) release in the hippocampus) were reversed. Undoubtedly, VEN inhibits depressive behaviours observed in the Porsolt test.⁴⁵ VEN owes its antidepressant effect to its effect on serotonin and dopamine levels in the striatum.^45,46 Modulation of GABA release in the hippocampus may, likewise, affect this drug’s antidepressant effect.⁴⁴

As for combined administration of ARI and VEN to the ADG, antidepressant effect was found both upon single and repeated administration of these drugs. Bhuvaneswari et al.⁴⁷ have proven antidepressant efficacy of sertraline and ARI combined administration. They have shown that mice receiving both preparations had a significantly reduced IT in the Porsolt test. Similar studies were conducted by Bourin et al.¹⁸ who studied combined administration of ARI with selective serotonin reuptake inhibitor (SSRI) antidepressants (sertraline, paroxetine, citalopram), serotonin - norepinephrine reuptake inhibitors (SNRIs) (VEN, minalcipram), norepinephrine reuptake inhibitors (NRIs) (desipramine) and bupropione. Study results have shown antidepressant effect of combined administration of ARI with antidepressants, except for bupropione and desipramine. Moreover, previous results show the possible enhanced antidepressant effect of using ARI in combined therapy with SSRI drugs. Studies suggest that enhanced antidepressant effect of ARI appears upon activation of 5-HT system and may be the evidence of a complex regulation between dopamine and 5-HT_1A and 5-HT_2A receptors.¹⁸

Analyses of locomotor activity of the animals have shown that ARI upon single administration in the ANG failed to cause any significant changes in the animals’ locomotor activity, which corroborates with our previous results.¹⁹ Different results were found by Zocchi et al.⁴⁸ who observed a reduced locomotor activity in rats given various doses of ARI. Changes in the animals’ mobility were observed only upon repeated administration of the drug (on day 14). Burda et al.²⁰ also observed a reduced activity of the animals upon repeated administration of the drug (14 days). This may be explained by studies by Wood et al.⁴⁹ who indicated that ARI in small doses (3.2 to 32 mg/kg) led to increased locomotor activity, while in large doses (above 100 mg/kg), it had a sedative effect. Increased locomotor activity of animals is probably caused by activation of dopaminergic receptor while sedation upon repeated administration is probably due to serotonin receptor inhibition. Studies have confirmed that ARI increases dopamine release in the prefrontal cortex and hippocampus of rat brains which may reduce negative symptoms and improve cognitive functions.^48,50 It is estimated that therapeutic efficacy of ARI in this area results from selective activation of dopaminergic neurotransmission in the prefrontal cortex.⁴⁸

Similarly to ARI, single administration of VEN had no effect on mobility of animals from the ANG. Identical conclusions were reached by Rogóz et al.³⁵ who failed to observe any changes in the animals’ locomotor activity upon single administration of VEN. Different results were obtained by Mitchella et al.⁵¹ who have shown sedative effect in mice upon single and repeated administration of VEN at the dose of 20 mg/kg. The author explained the sedative effect with inactivation of noradrenalin transporter by the antidepressants. No changes in the locomotor activity of animals may be due to low affinity of the drug to α₁ and H₁ receptors which may cause sedation.

ARI and VEN in combined (single) administration in the ANG did not cause any significant changes in the animals’ locomotor activity. This lack of effect is most probably caused by lack of activation of the dopaminergic receptor in the prefrontal cortex and lack of stimulation of noradrenergic receptors within the brain cortex, which change (usually increase) locomotor activity of animals. Locomotor activity may also be modulated by serotonin release from endings of serotoninergic fibres in the central part of the thalamus. References contain no reports on combined administration of ARI and VEN and their effect on the animals’ locomotor activity.

In prenatally stressed rats, ARI upon single administration reduced locomotor activity of the animals in the locomotor activity test, which corroborates with the previously obtained results for the animal schizophrenia model.¹⁹ Similar result was obtained also by Steed et al.⁵² upon analysis of various drug doses. Reduced locomotor activity in rats upon administration of ARI was also observed by Nordquist et al.⁵³ who explained it with behavioural changes induced by the use of dopamine agonists (apomorphine and amphetamine), N-Methyl-D-aspartic acid (NMDA) antagonists (MK-801, phencyclidine) and serotonin agonist (DOI). Tranquilizing effect is probably caused by a strong antagonistic effect of the drug on D₂ receptors in the mesolimbic route, which means that upon a dopamine release, ARI will inhibit the dopaminergic system.^19,54

Venlafaxing upon single administration to the ADG reduced locomotor activity of the animals. Similar results were obtained by Rogóz et al.³⁵ upon single administration of VEN to rats and mice, previously stimulated by administration of amphetamine, apomorphine or quinpirole to the animals. VEN’s sedative effect shown in the study may result from VEN’s stimulating effect on the serotoninergic and noradrenalin receptor. Neurotransmitters released from synaptic endings due to the drug’s effect remain in the synaptic cleft longer in concentration causing activation of postsynaptic receptors. Sedative effect observed in the study may have, therefore, appeared due to the drug’s small effect on the above-mentioned receptors.

ARI and VEN in combined (single) administration in the ADG reduced the animals’ locomotor activity. Appearance of sedation in the prenatally stressed group of animals may be caused by the inhibition of the dopaminergic receptor in the mesolimbic structures and weak effect of the drugs on adrenergic and cholinergic receptors. Reduced activity of the animals may also be due to inactivation of the noradrenalin transporter. Depression features an impaired function of brainstem neurotransmitters, mainly noradrenalin and serotonin. As far as dopamine is concerned, this neurotransmitter’s transduction in the neurons is enhanced. The disease increases dopaminergic tension in the mesolimbic structures (ARI is an antagonist in these structures) and reduces activity of this system in the mesocortical structures (ARI is a partial agonist here).⁵¹ As in the case of non-stressed rats, references contain no reports on combined administration of ARI and VEN and their effect on the animals’ locomotor activity in experimentally induced prenatal stress.

Conclusion

Results obtained in the conducted behavioural studies confirm ARI’s and VEN’s antidepressant effect and enhanced effect of these drugs when administered in combination. Analysis of disease pathogenesis and mechanism of action of the two drugs allows a conclusion that combined administration of ARI and VEN may have a positive effect on the therapy’s efficacy. They can be administered in combination in severe depression types and in schizophrenia with comorbid depression symptoms. Moreover, considering that both ARI and VEN belong to new classes of drugs, they are safe to use and have less adverse effects than conventional drugs which warrant their use in depression and schizophrenia. Further research is important, in particular using animal models of diseases, which undoubtedly expand the knowledge of mechanisms related to incidence of these diseases. In spite of methodological difficulties, research using animal models gives unlimited possibilities of studying many factors in controlled laboratory conditions.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

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