Decrease In Duration Of Immobility Research Articles

Prefrontal cortex-nucleus reuniens-hippocampus network exhibits sex-differentiated responses to stress and antidepressant treatment in rats.

Depression is a serious psychiatric disease, which is diagnosed twice as frequently in women than men. We have recently shown that lesioning or inactivation of the nucleus reuniens (RE), which interconnects the prefrontal cortex (PFC) and hippocampus, promoted resilience to stress in males, exerts an antidepressant effect in the Forced Swim Test (FST) and prevents the development of behavioral and neurobiological alterations induced by the chronic mild stress model of depression. In this study, we expand our findings on the FST in female rats and we investigate whether RE lesion presents sex differences following treatment with two distinct antidepressants, a selective serotonin reuptake inhibitor, i.e. sertraline and a tricyclic antidepressant, i.e. clomipramine. Male and female rats received either a surgical lesion of the RE or sham operation, then treated with vehicle, sertraline (10mg/kg) or clomipramine (10mg/kg) and were subjected to the FST. Activation of key brain areas of interest (PFC, Hippocampus and RE) were measured by c-Fos immunoreactivity. RE lesion induced an antidepressant-like phenotype in both female and male rats, confirming its crucial role in the stress response. Similarly to RE lesion, sertraline treatment resulted in increased swimming and decreased immobility duration, as well as enhanced head shake frequency, in both sexes. Notably, climbing behavior was increased only following clomipramine treatment. RE area was less active in females compared to male rats and in clomipramine-treated males compared to their corresponding vehicle-group. Activation of the PFC and the CA1 hippocampal area was reduced in clomipramine-treated females, in comparison to vehicle-treated female rats. This effect was not evident in males, which exhibited less activation in the PFC and the hippocampus than females. Re lesion proves equally effective in female and male rats, but sex is highlighted as a pivotal factor in behavioral and treatment response in FST, as well as in related circuit connectivity and activation.

The study of antidepressant properties of new 1,2,3-triazolo-1,4-benzodiazepine derivatives

Anxiety-depressive disorders are among the most common mental health conditions and often cause significant functional impairment, affecting a person’s quality of life. Research conducted in recent years indicate the importance of studying and searching for new substances based on benzodiazepines, in particular triazolobenzodiazepines, for the treatment of anxiety states and disorders, as well as determining the presence of other biological activities of these compounds. Aim. To study the antidepressant activity of new derivatives of 1,2,3-triazolo-1,4-benzodiazepines in the Porsolt forced swim and tail suspension tests. Materials and methods. The antidepressant activity of new 1,2,3-triazolo-1,4-benzodiazepine derivatives under the code MA-252, MA-253, MA-254, MA-255 and MA-261 was studied in the Porsolt forced swim and tail suspension tests. The following behavioral reactions, such as the latent period of the first immobility (more than 5 seconds), the total duration of immobility (staying in a stationary state), the number of immobile episodes, were recorded. Results and discussion. During the study, a decrease in the total duration of immobility, the main indicator of “despair” of animals, and an increase in the latent period of the first immobility were monitored. It may indicate the manifestation of antidepressant properties of new 1,2,3-triazolo-1,4-benzodiazepine derivatives. The indicator of the antidepressant activity in groups of animals administered MA-253, MA-254 and MA-255 derivatives in all doses was higher among the groups studied. The depression index was the lowest when MA-253 and MA-254 derivatives were used in the dose of 1 mg/kg, and was not statistically significantly different from that in the group receiving imipramine in the dose of 25 mg/kg. According to the results of the tail suspension test, 1,2,3-triazolo-1,4-benzodiazepine derivatives MA-253, MA-254 and MA-255 showed a significant decrease in the total duration of immobilization by 69.4 %, 47.1 % and 33.1 %, respectively, in relation to the control group (p<0.05), as well as an increase in the latent period of the onset of the first immobility episode by several times. Conclusions. A decrease in the duration of immobility in mice injected with 1,2,3-triazolo-1,4-benzodiazepine derivatives gives grounds to draw a conclusion that animals develop a state of “behavioral despair” and exhibit antidepressant properties.

Electroacupuncture attenuates LPS-induced depression-like behavior through kynurenine pathway.

A growing body of evidence suggests that inflammation and changes in glutamate neurotransmission are two pathophysiological mechanisms underlying depression. Electroacupuncture (EA) is a common therapeutic tool for the treatment of depression. However, the potential antidepressant mechanism of EA remains obscure. The change of the kynurenine pathway (KP) is the research priority of antidepressant mechanisms. This study will investigate the role of EA on lipopolysaccharide (LPS)-induced depression-like behavior and explore its possible mechanism of action. Lipopolysaccharide was used to induce depression-like behavior, and EA was given at Hegu (L14) and Taichong (LR3) acupoints in C57BL/6J mice. Depression-like behaviors were measured by behavioral tests, including tail suspension test (TST), sucrose preference test (SPT), force swim test (FST), and open field test (OFT). The levels of inflammatory cytokines IL-1β, IL-6, and TNF-α, and KP enzyme IDO1 were measured by qPCR and enzyme-linked immunosorbent assay (ELISA), while high-performance liquid chromatography (HPLC) was performed to detect the content of prefrontal cortex and hippocampal as well as serum glutamate, tryptophan (TRP), kynurenic (KYN), and quinolinic acid (QA). The results showed that (1) as evidenced by increased spontaneous locomotor activities, decreased immobility duration, and a stronger preference for sucrose in the sucrose preference test, EA reversed LPS-challenged depressive-like behavior. (2) EA at L14 and LR3 decreased the levels of inflammatory cytokines, inhibited IDO1, and regulated KP metabolisms, as well as lowered the concentration of glutamate. (3) EA may exert anti-depression effects by acting on the kynurenine pathway. This study evaluated the effects of EA on depression-like behaviors induced by lipopolysaccharide (LPS) and its regulation of inflammation and the glutamatergic system. Our results suggest that EA can ameliorate depression-like behaviors, lower the level of inflammation, and reduce the release of glutamate, possibly through the regulation of the kynurenine pathway in the brain.

The Influence of Environmental Enrichment on Affective and Neural Consequences of Social Isolation Across Development.

Social stress is associated with depression and anxiety, physiological disruptions, and altered brain morphology in central stress circuitry across development. Environmental enrichment strategies may improve responses to social stress. Socially monogamous prairie voles exhibit analogous social and emotion-related behaviors to humans, with potential translational insight into interactions of social stress, age, and environmental enrichment. This study explored the effects of social isolation and environmental enrichment on behaviors related to depression and anxiety, physiological indicators of stress, and dendritic structural changes in amygdala and hippocampal subregions in young adult and aging prairie voles. Forty-nine male prairie voles were assigned to one of six groups divided by age (young adult vs. aging), social structure (paired vs. isolated), and housing environment (enriched vs. non-enriched). Following 4 weeks of these conditions, behaviors related to depression and anxiety were investigated in the forced swim test and elevated plus maze, body and adrenal weights were evaluated, and dendritic morphology analyses were conducted in hippocampus and amygdala subregions. Environmental enrichment decreased immobility duration in the forced swim test, increased open arm exploration in the elevated plus maze, and reduced adrenal/body weight ratio in aging and young adult prairie voles. Age and social isolation influenced dendritic morphology in the basolateral amygdala. Age, but not social isolation, influenced dendritic morphology in the hippocampal dentate gyrus. Environmental enrichment did not influence dendritic morphology in either brain region. These data may inform interventions to reduce the effects of social stressors and age-related central changes associated with affective behavioral consequences in humans.

Antidepressant and Anxiolytic-Like Effects of the Stem Bark Extract of Fraxinus rhynchophylla Hance and Its Components in a Mouse Model of Depressive-Like Disorder Induced by Reserpine Administration.

There is an urgent need to find antidepressants that can be administered for long periods without inducing severe side effects to replace conventional antidepressants that control monoamine levels, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRI). We sought to determine the antidepressant effects of Fraxinus rhynchophylla Hance (F. rhynchophylla Hance, FX) and its components on a reserpine-induced mouse model. One hour after oral administration of FX (30, 50, and 100 mg/kg), esculin (50 mg/kg), esculetin (50 mg/kg), fraxin (50 mg/kg), and fluoxetine (20 mg/kg), reserpine was delivered intraperitoneally to mice. Behavioral experiments were conducted to measure anxiety and depressive-like behaviors after 10 days of administration. FX and its components increased the number of entries into the center of an open field as well as distance traveled within it and decreased immobility duration in the forced swim and tail suspension tests. Reserpine-induced increases in plasma corticosterone concentrations were attenuated by the administration of FX and its components, which were also found to decrease the reserpine-induced enhancement of mRNA levels of interleukin (IL)-12 p40, IL-6, and tumor necrosis factor (TNF)-α, pro-inflammatory cytokines. Finally, the diminished expressions of hippocampal phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) by reserpine were increased by FX and its components. Our results suggest that FX and its components regulate anxiety and depressive-like behaviors through stress hormones, immune regulation, and the activation of neuroprotective mechanisms, further supporting the potential of FX and its components as antidepressants.

Alginate nanogels-based thermosensitive hydrogel to improve antidepressant-like effects of albiflorin via intranasal delivery

Depression is a primary public health problem. However, current antidepressants work slowly, and together with side effects. Herein, the alginate nanogels were constructed to load albiflorin (albiflorin nanogels), which further formed albiflorin nanogel loaded self-assembled thermosensitive hydrogel system (albiflorin-NGSTH) and were used to improve its antidepressant effects. The nanogel showed a nano-scaled particle size and stronger antioxidant activity. Rheological studies showed that albiflorin-NGSTH had a sol-gel transition at approximately 28 °C. Albiflorin-NGSTH quickly entered the brain by intranasal delivery, and had a continuously release for albiflorin. Preliminary results of mice behavioral despair tests found that albiflorin-NGSTH had no effects on independent exploratory behavior and anxiety of the mice, and significantly decreased immobility duration of the mice in tail suspension test (TST). Moreover, the intranasally administrated albiflorin-NGSTH at a low dose improved depressive behavior, decreased levels of proinflammatory cytokines, and repaired neuronal damage of chronic unpredictable mild stress (CUMS) rats, which indicated an excellent potential for depression therapy. The treatment of albiflorin-NGSTH on depressive disorder was achieved by regulating signal pathway related to depression. Therefore, albiflorin-NGSTH has an excellent potential for clinical application in intranasal drug delivery systems.

Neuropharmacological evaluation of methanolic extract of Costus speciosus Linn. rhizome in Swiss albino mice

Objective: To evaluate the neuropharmacological properties of Costus speciosus (C. speciosus) rhizome using different experimental mouse models. Methods: The anxiolytic effect was investigated by hole-board test, elevated plus maze and light/dark test, while central nervous system (CNS) depressant effect was evaluated by thiopental sodium-induced sleep test. Finally, antidepressant effect was evaluated by forced swimming test and tail suspension test. Results: In both elevated plus maze and hole board test, 400 mg/kg C. speciosus showed more significant CNS depressant effect than 1 mg/kg diazepam. Both 200 mg/kg and 400 mg/kg C. speciosus extract produced a significant dose-dependent decrease in onset of sleep. In forced swimming test, C. speciosus rhizome showed a decrease in duration of immobility in a dose-dependent manner. Imipramine (10 mg/kg) and C. speciosus extract at 400 mg/kg dose exhibited a significant reduction in duration of immobility in tail suspension test which provided additional evidence of antidepressant effect of C. speciosus rhizome. Conclusions: Our study indicates that C. speciosus rhizome possesses CNS depressant, anxiolytic and antidepressant-like activities. Further studies are warranted determine the exact phytoconstituents and mechanism of action responsible for the neuropharmacological effect.

Antidepressant Effects of Rosemary Extracts Associate With Anti-inflammatory Effect and Rebalance of Gut Microbiota.

It is currently believed that inflammation acts as a central part in the pathophysiology of depression. Rosemary extracts (RE), the crucial active constituents extracted from Rosmarinus officinalis Linn, have drawn wide concerns because of their potential for anti-inflammatory effects. However, no study has highlighted the antidepressant effects of RE on chronic restraint stress (CRS) mice, and the inflammatory mechanisms related to gut microbiome have not yet been elucidated. This study showed that depressive-like behaviors, gut microbiota dysbiosis, and activation of inflammatory reactions in the hippocampus and serum of CRS mice, as well as activation of inflammatory reactions in BV-2 microglia cells induced by lipopolysaccharide (LPS), could be attenuated by RE. We found that the pretreatment with RE increased the time in the center of open field test (OFT), and decreased immobility duration in tail suspension test (TST) as well as forced swimming test (FST). Furthermore, RE enhanced the sequences proportion of Lactobacillus and Firmicutes, and reduced the sequences proportion of Bacteroidetes and Proteobacteria in feces. Moreover, RE obviously suppressed protein expression of IL-1β, TNF-α, p-NF-κ B p65 and Iba1 in hippocampus, and elevated BDNF as well as p-AKT/AKT expression. Importantly, pre-incubation with RE protected microglia by alleviating protein expression of IL-1β, TNF-α and p-NF-κ B p65 induced by LPS. Additionally, RE downregulated the level of IL-1β and TNF-α in serum. In conclusion, this study showed the antidepressant effects of RE are mediated by anti-inflammatory effects in hippocampus, serum and BV-2 microglia as well as rebalancing gut microbiota.

Study of Antinociceptive, Antipyretic and Neuropharmacological Activities of Leaf Extracts of Citrus assamensis

The present study was executed to explore in vivo antinociceptive, antipyretic and neuropharmacological activities of different leaf extracts of Citrus assamensis in Swiss albino mice. C. assamensis leaf extract displayed marked dose dependent antinociceptive potential in the five pain models. All leaf extracts except chloroform (200 mg/kg body weight) extract, produced significant (**p<0.01, ***p<0.001) antinociception against thermal induced pain stimuli in mice at various time points of post treatment in hot plate study compared to the control group. In acetic acid induced writhing assay, methanol (100 mg/kg body weight) and chloroform (200 mg/kg body weight) extracts showed significant (*p<0.01) result. In tail immersion test, basal reaction time was found significant (*p<0.01) in case of ethanol (100 mg/kg body weight) and chloroform (200 mg/kg body weight) extracts compared against control. Both the doses of all the extracts exhibited significant (***p<0.001) activity in formalin induced paw licking as well as percent inhibition of glutamate induced writhing study. Both the doses of methanol and ethanol extracts showed significant (*p<0.05) results in decreasing in rectal temperature after 1 hr. Higher doses of all the extracts showed significant (*p<0.05) decrease in duration of immobility in foreed swimming test (FST). The higher dose of ethanol extract (200 mg/kg body weight) significantly (*p<0.05) decreased the rate of movement with time in open field test. The test samples displayed marked antinociceptive potential in all the test procedures and also displayed marked antipyretic and neuropharmacological activities at different test doses.Bangladesh Pharmaceutical Journal 21(2): 87-95, 2018

ANTI-DEPRESSANT EFFECT OF CEFTRIAXONE IN FORCED SWIMMING TEST AND IN TAIL SUSPENSION TEST IN MICE

Objective: Depression is a major psychiatric disorder affecting nearly 350 million people worldwide and imposes a substantial health burden on the society. Ceftriaxone has demonstrated neuroprotective effects in animals. It has also undergone trials as a treatment option for amyotrophic lateral sclerosis. This study was therefore undertaken to evaluate the antidepressant-like effect of ceftriaxone in mice.Methods: Ceftriaxone was administered at three different doses (0.130, 0.195 and 0.260g/kg) to Swiss albino mice of either sex by intra peritoneal (i. p.) route. The period of immobility in control and drug-treated mice were recorded in forced swimming test (FST) and tail suspension test (TST). The antidepressant effect of ceftriaxone indicated by the decrease in duration of immobility was compared to that of fluoxetine (0.020 g/kg, i. p.).Results: Ceftriaxone decreased the duration of immobility in mice. It showed a significant dose-dependent antidepressant effect. The antidepressant effect of 0.260g/kg of ceftriaxone was comparable to that of fluoxetine in the TST but not in the FST.Conclusion: The results of the present study indicate antidepressant activity of Ceftriaxone. The study shows that ceftriaxone has additional action on the central nervous system other than neuroprotection. Ceftriaxone therapy in cases of encephalomeningitis and in various cases of hemorrhages in the brain can, therefore, prevent the development of depression in future

Studies on the reproductive effects of chronic treatment with agomelatine in the rat

Agomelatine is an antidepressant with a novel mechanism of action. It is a melatonergic agonist for MT1 and MT2 receptors and a serotonin (5-HT2C) receptor antagonist. Agomelatine has been suggested not to have adverse effects on sexual functions. However, the effects of chronic agomelatine administration on reproductive functions have not been sufficiently studied in animal models. We mainly aimed to explore the effects of agomelatine on reproductive functions in the male and female rats. For the experimental studies, Sprague Dawley rats were used. The animals started to receive daily oral agomelatine (10mg/kg) on post-natal day 21. Agomelatine advanced vaginal opening in the female rats whereas it delayed puberty onset in the male rats. Agomelatine treatment significantly decreased intromission frequencies, which indicates a facilitator role of this antidepressant on male sexual behavior. In the forced swimming test (FST) used for assessing antidepressant efficacy, agomelatine induced a significant decrease in duration of immobility, and an increase in the swimming time, respectively, which confirms the antidepressant-like activity of agomelatine. The present findings suggest that agomelatine shows a strong antidepressant effect in the male rats without any adverse influences on sexual behavior, and its effects on pubertal maturation seem to show sex-dependent differences.

Effect of Punica granatum on behavior in rats

The importance of diet in depression is now increasingly recognized, since balanced diet not only reduces the risk of various chronic diseases but also promotes normal development and functioning of all systems including brain. Hence the present study was designed to observe the effect of three doses of Punica granatum 2, 5 and 8 ml/kg on the behavioral changes in rats, particularly anxiolytic and antidepressant activity. During 15 days study, experimental paradigm for anxiety and depression were assessed twice using open field, elevated plus maze and forced swimming test. In open field, distance travelled, number of centre entries and number of rearing’s were increased. In elevated plus maze, number of open arm entries were increased and in forced swimming test, there was decrease in duration of immobility and increase in duration of climbing. All these changes were significant at moderate and high doses of P. granatum. Thus it may be suggested that P. granatum possesses anxiolytic and antidepressant activity at moderate and high doses. Key words: Punica granatum, anxiolytic, antidepressant.

Behavioral effects of Citrus limon in rats.

Anxiety and depression are increasing worldwide, however these disorders may be managed by making healthier changes is dietary pattern, since there are evidences that diet rich in antioxidants and vitamins help reduce anxiety and depression. Hence present study was designed to evaluate the behavioral effects of Citrus limon in rats at three different doses i.e. 0.2, 0.4 and 0.6 ml/kg considered as low, moderate and high doses. Anxiolytic and antidepressant activities were specifically assessed twice during 15 days using open field test, elevated plus maze and forced swimming test. In open field test C. limon, revealed increase in distance travelled, number of central entries and number of rearing's at moderate dose, while in the elevated plus maze, number of open arm entries were found to be increased. Whereas in forced swimming test, there was decrease in duration of immobility and increase in duration of climbing. Thus results of present study suggest that C. limon at moderate dose have anxiolytic effect.

Antidepressant activity of brahmi in albino mice.

In traditional system of medicine brahmi has been used to enhance memory. Recently it has been reported to have action in psychiatric disorders. With these backgrounds the work has been undertaken to study antidepressant activity of brahmi in albino mice. To evaluate antidepressant activity of brahmi in experimental models. The antidepressant activity was studied in albino mice using forced swimming test (FST), tail suspension test (TST) and shock induced depression (SID). Imipramine (10mg/kg), fluoxetine (30mg/kg) were used as standard drugs and brahmi (10, 20, 30mg/kg) was used as test drug. Brahmi exhibited significant decrease in duration of immobility in FST and reduced the shock induced decrease in activity in SID models. It didn't show any activity in the TST model. Brahmi has shown antidepressant activity in FST and SID.

Supplementation of omega-3 fatty acids with aripiprazole and lithium lessens methylphenidate induced manic behavior in Swiss albino mice

Bipolar disorder (BD) is a severe neuropsychiatric disorder, affecting approximately 1–2% of the world population. The present study designed to investigate whether omega-3 fatty acids could impinge the effect of methylphenidate (MPD) induced mania in mice after treatment with aripiprazole and lithium. Mice were subjected to mania paradigm daily for a period of 14 days to induce mania-like behavior by administration of MPD. The effect of supplementation of omega-3 fatty acids on MPD induced mania mice was examined by behavioral analysis such as open field test, forced swim test and actophotometer test. Supplementation of omega-3 fatty acids with aripiprazole and lithium reduced methylphenidate-induced hyperlocomotion. As a result MPD causes mania-like behavior in mice, as indicated by significant decrease in duration of immobility in forced swim test. Supplementation of omega-3 fatty acids (1.5 ml/kg), aripiprazole (1.5 mg/kg), lithium (50 mg/kg), significantly reduced the acute administration of MPD (5 mg/kg) induced mania-like behavior in open field test. Based on the behavioral analysis mice shows decreased total locomotion, duration of immobility time and the locomotor counts. In conclusion, the results of the present study suggested that omega-3 fatty acids supplementation alleviated the MPD-induced manic behavior in mice.

Sertraline behavioral response associates closer and dose-dependently with cortical rather than hippocampal serotonergic activity in the rat forced swim stress

The rat Forced Swim Test (FST) is widely used to investigate the response to antidepressant treatment. Selective serotonin reuptake inhibitors (SSRIs) elongate swimming duration during the FST, while climbing duration is unaffected. In the present study, we aimed to correlate behavioral effects of the SSRI sertraline in the FST with respective changes in the serotonergic activity of the hippocampus and the prefrontal cortex. Male rats were subjected to the standard FST (two swim sessions in two consecutive days) and between the two sessions they received three i.p. injections of sertraline (10mg/kg or 40mg/kg) or vehicle. All rats were killed immediately after the second FST session. Unstressed animals received the same administration schemes and were killed in equivalent time-points. Serotonin and its metabolite 5-HIAA were assayed in the hippocampus and the prefrontal cortex with the use of high-performance liquid chromatography (HPLC-ED) and their ratio 5-HIAA/5-HT was calculated. Sertraline enhanced swimming and decreased immobility duration at both doses. Serotonergic activity was not altered by the 2-day swim stress in either brain region, while subchronic sertraline treatment enhanced 5-HT levels and decreased 5-HIAA/5-HT in the hippocampus and the prefrontal cortex. The serotonin turnover rate (5-HIAA/5-HT ratio) decrease is probably indicative of reduced 5-HT metabolism, as a result of 5-HT reuptake inhibition. This effect was significant in the prefrontal cortex of unstressed rats only after a higher dose of sertraline. In the prefrontal cortex, but not in the hippocampus, immobility duration was negatively correlated with 5-HT tissue levels, whereas swimming duration was positively correlated with 5-HT. These results indicate that after antidepressant treatment, behavior during the FST can be predictive of respective serotonergic changes, especially in the prefrontal cortex.

Antidepressants differentially modify the extinction of an aversive memory task in female rats

Treatment of major depression, posttraumatic stress disorder and other psychopathologies with antidepressants can be associated with improvement of the cognitive deficits related to these disorders. Although the mechanisms of these effects are not completely elucidated, alterations in the extinction of aversive memories are believed to play a role in these psychopathologies. We have recently verified that female rats present low levels of extinction when submitted to the plus-maze discriminative avoidance task. In the present study, female rats were treated long term with clinically used antidepressants (fluoxetine, nortriptyline or mirtazapine) and subjected to the plus-maze discriminative avoidance task to evaluate learning, memory, extinction and anxiety-related behaviors as well as behavioral despair in the forced swimming test. All groups learned the task and exhibited retrieval. Chronic treatment with fluoxetine (but not with the other antidepressants tested) increased extinction of the discriminative task. In the forced swimming test, the animals treated with fluoxetine and mirtazapine showed decreased immobility duration. In conclusion, fluoxetine potentiated extinction, while both fluoxetine and mirtazapine were effective in ameliorating depressive-like behavior in the forced swimming test, suggesting a possible dissociation between the effects on mood and the extinction of aversive memories in female rats.

C.12.04 Clinical experience with agomelatine in depressed patients

Agomelatine is an antidepressant with a novel mechanism of action. It is a melatonergic agonist for MT1 and MT2 receptors and a serotonin (5-HT2C) receptor antagonist. Agomelatine has been suggested not to have adverse effects on sexual functions. However, the effects of chronic agomelatine administration on reproductive functions have not been sufficiently studied in animal models. We mainly aimed to explore the effects of agomelatine on reproductive functions in the male and female rats. For the experimental studies, Sprague Dawley rats were used. The animals started to receive daily oral agomelatine (10 mg/kg) on post-natal day 21. Agomelatine advanced vaginal opening in the female rats whereas it delayed puberty onset in the male rats. Agomelatine treatment significantly decreased intromission frequencies, which indicates a facilitator role of this antidepressant on male sexual behavior. In the forced swimming test (FST) used for assessing antidepressant efficacy, agomelatine induced a significant decrease in duration of immobility, and an increase in the swimming time, respectively, which confirms the antidepressant-like activity of agomelatine. The present findings suggest that agomelatine shows a strong antidepressant effect in the male rats without any adverse influences on sexual behavior, and its effects on pubertal maturation seem to show sex-dependent differences.

Shaping brain development: Mouse communal nesting blunts adult neuroendocrine and behavioral response to social stress and modifies chronic antidepressant treatment outcome

Early experiences shape brain function and behavior and, consequently, vulnerability to psychopathology at adulthood. Here we exploited the mouse communal nest (CN) paradigm in order to investigate the effect of the early social environment on the emergence of endophenotypes of depression and on antidepressant efficacy at adulthood. CN, which consists in a single nest where three mothers keep their pups together and share care-giving behavior until weaning, is characterized by high levels of maternal behavior and peer interactions, thus representing an highly stimulating environment. Our results show that, when compared to mice reared in standard laboratory conditions (SN), adult CN mice exhibited greater sucrose preference on the first days of the test, displayed reduced anhedonia during social stress and had lower corticosterone levels after acute and prolonged social stress. Furthermore, in line with previous work, CN displayed longer immobility than SN mice in the forced swim test. Here we show that such behavioral response is differently affected by antidepressants according to early experiences. A 3-week fluoxetine treatment affected only SN mice, leading to an increase of immobility duration up to the levels showed by CN mice, while acute fluoxetine administration decreased immobility duration in both groups. These results show that being reared in a CN profoundly changes developmental trajectories, reducing the adult display of endophenotypes of depression and modifying response to antidepressants. The present findings suggest that early experiences represent one of those factors to be taken into account to identify the appropriate individual pharmacological strategy to treat depression in patients.

Modulation by sudden darkness of apomorphine-induced behavioral responses

Sudden darkness increases motor activity and decreases anxiety. In the present study, we focused on the role of dopaminergic mechanisms involved in the effects of sudden darkness. The influence of sudden darkness on the behavioral effects of low (0.05 and 0.1 mg/kg) and high (0.25, 0.45 and 0.6 mg/kg) doses of apomorphine (APO) was tested. We assayed the effects of low APO doses on yawning–penile erection syndrome (YES; 0.05 and 0.1 mg/kg) and on motor activity (0.05 mg/kg), and the effects of high APO doses on motor activity (0.25 mg/kg) and stereotyped behavior (0.45 mg/kg and 0.6 mg/kg). Spontaneous total and genital grooming of male and female rats were also recorded. Sudden darkness modified some spontaneous behaviors and also modulated several APO-induced behavioral effects. It increased spontaneous total grooming and genital grooming in male rats but had no effect on these parameters in female rats. These results show sexual dimorphism for total and genital grooming in both control and sudden darkness conditions. APO was able to induce YES in a dose-dependent manner. Sudden darkness decreased yawning elicited by both 0.05 and 0.1 mg/kg of the drug. No other parameter of YES was modified. In the open-field test, sudden darkness increased total locomotion and rearing and decreased immobility duration. APO at a dose of 0.05 mg/kg had the opposite effect on these parameters under light conditions; none of them were modified by sudden darkness. Animals treated with APO at 0.25 mg/kg, a dose that augmented total locomotion and rearing and diminished immobility duration, were clearly divided into two groups according to their responses, i.e., hypo- and hyper-responsive rats. Sudden darkness improved total locomotion and rearing, reduced immobility duration and total grooming in the hyporesponsive group, and showed no effects on the hyper-responsive group. Sudden darkness caused no modifications of stereotyped behavior. These results may be due to a sudden darkness-induced physiological release of dopamine that diminishes pre-synaptic responses to APO and increases low-intensity post-synaptic responses such as motor activity without modifying high-intensity post-synaptic responses such as stereotyped behavior.