Antidepressants In Animal Models Research Articles

A New Augmentation Strategy against Depression Combining SSRIs and the N-terminal Fragment of Galanin (1-15).

Depression is one of the most disabling mental disorders, with the second highest social burden; its prevalence has grown by more than 27% in recent years, affecting 246 million in 2021. Despite the wide range of antidepressants available, more than 50% of patients show treatment-resistant depression. In this review, we summarized the progress in developing a new augmentation strategy based on combining the N-terminal fragment of Galanin (1-15) and SSRI-type antidepressants in animal models.

BDNF, A Focus to Major Depression

Major depressive disorder is characterized, among other symptoms, by depressed mood and anhedonia associated with a high rate of suicidal ideation. In recent years, research has shown reduced expression of the brain-derived neurotrophic factor (BDNF) in limbic areas of individuals with depression. This reduction of BDNF is reversed by antidepressants in animal models of stress. Stress is one of the main triggers of mood disorders such as depression. Also, administration of BDNF increases the number of serotonergic fibers and serotonergic innervation, indicating an increase of serotonin in the synaptic cleft by this neurotrophin. Thus, BDNF appears to be one of the targets of antidepressant drugs for the increase of monoamines and remission of symptoms of major depression. The purpose of this review was to show the evidence that indicates BDNF as a molecular substrate for vulnerability to depression and the response of this substrate to the antidepressants.

Nitric oxide: Antidepressant mechanisms and inflammation.

Millions of individuals worldwide suffers from mood disorders, especially major depressive disorder (MDD), which has a high rate of disease burden in society. Although targeting the biogenic amines including serotonin, and norepinephrine have provided invaluable links with the pharmacological treatment of MDD over the last four decades, a growing body of evidence suggest that other biologic systems could contribute to the pathophysiology and treatment of MDD. In this chapter, we highlight the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby treatment of MDD. This has been investigated over the last four decades by showing that (i) levels of NO are altered in patients with major depression; (ii) modulators of NO signaling exert antidepressant effects in patients with MDD or in the animal studies; (iii) NO signaling could be targeted by a variety of antidepressants in animal models of depression; and (iv) NO signaling can potentially modulate the inflammatory pathways that underlie the pathophysiology of MDD. These findings, which hypothesize an NO involvement in MDD, can provide a new insight into novel therapeutic approaches for patients with MDD in the future.

Depression Assessment in Clinical Trials and Pre-clinical Tests: A Critical Review.

Depression is deeply rooted in human behavior. The development of new antidepressants demands the creation of animal models to investigate new drugs, which potentially could work as antidepressants. The aim of this review is to discuss the different ways of assessing depression in clinical research, including clinical trials, and the different animal behavioral tests used to study depression and test the efficacy of antidepressants in pre-clinical studies. In clinical practice, a categorical classification, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD) can be used for diagnosis, through the use of structured and semi-structured interviews. On the other hand, depression can also be assessed using a dimensional approach, through self- or clinicianrated questionnaires. Regarding the assessment of the efficacy of antidepressants in animal models, several tests are routinely used, namely the Forced Swim Test, the Modified Forced Swim Test, the Tail Suspension Test and the Sucrose Preference Test. These tests are informative, providing that the following rules are taken into account: 1) more than one test is used, with coherent results; 2) secondary drug effects, the most frequent being putative changes in motor activity, are taken into account and properly controlled with specific tests run concomitantly; 3) each test and specific protocol is validated with data from at least a gold standard antidepressant drug. We herein briefly discuss the potential and limitations of each of those tests.

Coadministration of ketamine with conventional antidepressants in animal models of depression

Background: Mental health has become one of the thrust areas for research given the complexity of the human mind and paucity of treatment strategies to handle its dysfunction effectively. The mental disorders gain prominence due to the damage they can cause to the individual themselves, the people who are in contact with them and to the society at large. Depression is a mental disorder which is encountered frequently and needs immediate attention. Conventional antidepressants such as selective serotonin reuptake inhibitor and tricyclic antidepressants are used in the management of depression. These drugs have a poor safety profile, take time for therapeutic response and have issues with patient compliance as a concern. Hence, it is postulated that concurrent administration of ketamine with conventional antidepressants would relieve the effects of depression more rapidly, would lower the dose of the later and would be more efficacious. Aims and Objectives: To study the antidepressant effect of coadministration of ketamine with conventional antidepressants in animal models of depression. Materials and Methods: The study was a randomized controlled animal study done on 36 male albino BALB/c mice divided into six groups, namely, Group A distilled water i.p., Group B imipramine 10 mg/kg (i.p.), Group C ketamine 10 mg/kg, Group D escitalopram 5 mg/kg (i.p.), Group E imipramine 10 mg/kg (i.p.) and ketamine 10 mg/kg (i.p.), and Group F escitalopram 5 mg/kg (i.p.) and ketamine 10 mg/kg (i.p.), respectively. The animal model used was the forced swim test. The reduction in immobility time was taken as the guide for the antidepressant effect. Results: The data were analyzed with the one-way ANOVA test using SPSS version 18. The results showed a significant reduction in immobility time and a statistical significance between the groups (P = 0.017). A post-hoc test showed that all the groups, i.e., B, C, D, E, and F significantly reduced the immobility time in comparison with the control Group A. Conclusion: The above results support the fact that coadministration of ketamine can be a treatment modality for the management of depression with the advantage of quicker onset of action.

S.06.03 - Evaluation of NMDA signalling modifiers as putative antidepressants in animal models

S.06.03 - Evaluation of NMDA signalling modifiers as putative antidepressants in animal models

Study of the sexual dysfunction secondary to antidepressants in animal models

IntroductionSexual dysfunction is a very important problem in western countries. One of the causes is the treatment with antidepressants; most of the currently available produce sexual dysfunction in men and women (lower libido, anorgasmia, etc.).ObjectiveComparing the nervous system of the animals we expect to find differences to explain the biological substratum of the sexual dysfunction that produce the selective serotonin reuptake inhibitors.MethodTwenty Wistar rats; approximate weight 150 g. It is divided into 4 groups: 2 experimental (paroxetine and agomelatina mouth) and 2 controls. There is a daily conduct. Weighing at the beginning of the study, 14 and 28 days. Is performed sacrifice by decapitation, is extracted from the brain and after fixing paraffin cuts are carried out for their subsequent staining (immunohistochemistry) with their corresponding murine antibody and viewing through optical microscope.ResultsLower immunoreactivity with the antibody anti-TH in the animals treated with paroxetine, at all levels of the dopaminergic activity (tracks mesolimbica, cortical circuit, nigrostriatal pathway and tubero-infundibular). This decrease is reaffirmed after the statistical treatment of data.ConclusionsTreatment with paroxetine in animal models causes a depletion of the dopaminergic system that can be one of the biological bases of sexual dysfunction, altering the reward mechanisms as well as producing hyperprolactinemia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta-analysis.

Poststroke depression is a prevalent complication of stroke with unclear pathogenesis. The benefits of antidepressants in this context and their effects on stroke recovery other than effects on mood are not clearly defined, with some studies suggesting efficacy in improving functional outcome in both depressed and nondepressed stroke patients. We have analyzed the preclinical animal data on antidepressant treatment in focal cerebral ischemia, modeled±depression, to help inform clinical trial design. We performed a systematic review and meta-analysis of data from experiments testing the efficacy of antidepressants versus no treatment to reduce infarct volume or improve neurobehavioral or neurogenesis outcomes in animal models of stroke. We used random-effects metaregression to test the impact of study quality and design characteristics and used trim and fill to assess publication bias. We identified 44 publications describing the effects of 22 antidepressant drugs. The median quality checklist score was 5 of a possible 10 (interquartile range, 4-7). Overall, antidepressants reduced infarct volume by 27.3% (95% confidence interval, 20.7%-33.8%) and improved neurobehavioral outcomes by 53.7% (46.4%-61.1%). There was little evidence for an effect of selective serotonin reuptake inhibitors on infarct volume. For neurobehavioral outcomes there was evidence of publication bias. Selective serotonin reuptake inhibitors were the most frequently studied antidepressant subtype and improved neurobehavioral outcome by 51.8% (38.6%-64.9%) and increased neurogenesis by 2.2 SD (1.3-3.0). In line with current clinical data and despite some limitations, antidepressant treatments seem to improve infarct volume and neurobehavioral outcome in animal models of ischemic stroke.

P.2.e.002 Vortioxetine (Lu AA21004), a multimodal antidepressant: differentiation from current antidepressants in animal models of depression

Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess – a competitive mind game requiring highly complex cognitive skills – can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2×200 mg modafinil, 2×20 mg methylphenidate, and 2×200 mg caffeine or placebo in a 4×4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players’ strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.

The Hippocampus, Neurotrophic Factors and Depression

Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants. Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary-adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 3-4 weeks of administration, the time course for maturation of new neurons. The ablation of hippocampal neurogenesis blocks the behavioural effects of antidepressants in animal models. The above findings suggest new possible targets for the pharmacotherapy of depression such as neurotrophic factors, their receptors and related intracellular signalling cascades; agents counteracting the effects of stress on hippocampal neurogenesis (including antagonists of corticosteroids, inflammatory cytokines and their receptors); and agents facilitating the activation of gene expression and increasing the transcription of neurotrophins in the brain.

The acute and chronic effects of combined antipsychotic–mood stabilizing treatment on the expression of cortical and striatal postsynaptic density genes

The detection of changes in postsynaptic gene expression after the administration of mood stabilizers, alone or in combination with antipsychotics, and antidepressants in animal models of drug treatment, may represent a valuable strategy to explore the molecular targets of the mainstay treatments for bipolar disorder. In this study we investigated, in both acute and chronic paradigms, the expression of specific postsynaptic density genes (Homer1a, Homer1b/c, and PSD95) and genes putatively implicated in mood stabilizers mechanism of action (GSK3b, ERK) after administration of first (haloperidol) or second generation antipsychotics (quetiapine 30mg/kg), alone or in combination with valproate. Moreover, we compared the effects of an antidepressant agent widely used in bipolar depression (citalopram) with a low dose of quetiapine (15mg/kg), which has been demonstrated to display antidepressant action in bipolar depression.In striatal regions, Homer1a expression was strongly induced by haloperidol compared to all the other treatments. Haloperidol plus valproate also markedly induced Homer1a, but to a significant lesser extent than haloperidol alone. Also in the chronic paradigm haloperidol, but not haloperidol plus valproate, induced Homer1a expression in all the subregions of the caudate-putamen and in the nucleus accumbens core. The high dose of quetiapine significantly induced Homer1a in anterior cingulated, premotor and motor subregions of the cortex, and the extent of induction was significantly higher as compared to the lower dose. Oppositely, Homer1a expression was decreased in the cortex by citalopram acute administration.ERK gene was upregulated in cortex and striatum by the acute treatment with valproate and with the combination of haloperidol or quetiapine plus valproate, whereas no significant differences were noticed in GSK3b expression among treatments. PSD95 showed a significant upregulation by acute citalopram and by haloperidol plus valproate in both cortical and subcortical regions. Haloperidol and quetiapine 30mg/kg, oppositely, significantly reduced the expression of the gene in the cortex.In conclusion, these results suggest that the combined treatment with a typical or an atypical antipsychotic plus valproate may induce differential modulation of postsynaptic genes expression when compared to the effects of these drugs individually administered.

Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress

The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression. The survival of newly born hippocampal neurons is decreased by chronic psychosocial stress and increased by exposure to enriched environments. These observations suggest the existence of a link between hippocampal neurogenesis, stress-induced behavioral changes, and the beneficial effects of enriched environment. To show causality, we subjected transgenic mice with conditionally suppressed neurogenesis to psychosocial stress followed by environmental enrichment. First, we showed that repeated social defeat coupled with chronic exposure to an aggressor produces robust and quantifiable indices of submissive and depressive-like behaviors; second, subsequent exposure to an enriched environment led to extinction of the submissive phenotype, while animals exposed to an impoverished environment retained the submissive phenotype; and third, enrichment was not effective in reversing the submissive and depressive-like behaviors in transgenic mice lacking neurogenesis. Our data show two main findings. First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis.

Regulation of adult hippocampal neurogenesis: relevance to depression

Recent hypotheses suggest that depression may involve an inability to mount adaptive structural changes in key neuronal networks. In particular, the addition of new neurons within the hippocampus, a limbic region implicated in mood disorders, is compromised in animal models of depression. Adult hippocampal neurogenesis is also a target for chronic antidepressant treatments, and an increase in adult hippocampal neurogenesis is implicated in the behavioral effects of antidepressants in animal models. The ‘neurogenic’ hypothesis of depression raises the intriguing possibility that hippocampal neurogenesis may contribute to the pathogenesis and treatment of depressive disorders. While there remains substantial debate about the precise relevance of hippocampal neurogenesis to mood disorders, this provocative hypothesis has been the focus of many recent studies. In this review, we discuss the pathways that may mediate the effects of depression models and antidepressants on adult hippocampal neurogenesis, and the promise of these studies in the development of novel antidepressants.

Antidepressant-like effects in various mice strains in the tail suspension test

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion. The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2 mg/kg) and C57BL/6J Rj to paroxetine (from 0.5 mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8 mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8 mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.

Role of 5-HT 1B receptors in the activity of antidepressants in animal models

Role of 5-HT 1B receptors in the activity of antidepressants in animal models

Noradrenergic and opioid mediation of tricyclic-induced reversal of escape deficits caused by inescapable shock pretreatment in rats.

The present study was undertaken to investigate the possible involvement of a noradrenergic and opioid mediation of the reversal by tricyclic antidepressants of escape deficits produced by inescapable shock pretreatment. Rats were first exposed to 60 inescapable shocks (15 s duration, 0.8 mA, every min +/- 15 s) and 48 h later subjected, to daily shuttle-box sessions (30 trials/day, ITI: 30 s) during 3 consecutive days. Twice-daily IP injection of desipramine or clomipramine (total daily dose: 32 mg/kg) prevented escape deficits. Penbutolol (0.125; 0.25; 0.5 mg/kg), prazosin (1; 2 mg/kg) and naloxone (0.5; 1 mg/kg) given once a day dose-dependently attenuated the beneficial effect of tricyclic antidepressants in reducing the number of escape failures in rats exposed to shock pretreatment. In agreement with data obtained in the forced-swimming model, these findings support the notion that activation of noradrenergic and opioid receptors is an important factor in the mediation of the effects of tricyclic antidepressants in animal models of depression.