Forced Swimming Test In Rats Research Articles

Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats

Neural circuits involved in the development of depression are currently poorly understood. To provide insight into this issue, we evaluated the influence of seven clinically effective antidepressants on neuronal activity in thirty rat brain areas. Drugs belonging to all major groups of antidepressants (imipramine, reboxetine, fluoxetine, bupropion, mirtazapine, agomelatine, and phenelzine) were examined; since antidepressants typically require weeks of continued administration before they achieve a therapeutic effect, we administered these drugs for 21 days. The experiments were conducted with male Wistar rats. To identify the neuroanatomical targets for antidepressants, the alterations of c-Fos expression in different brain areas were measured using ELISA assay. The drugs were examined at doses sufficient to produce behavioral effect in the rat forced swim test (FST). All the drugs at the behaviorally relevant doses activated two brain areas, the lateral entorhinal cortex and dorsal subiculum of the hippocampus; none of the drugs affected the c-Fos expression in the medial orbital, prelimbic and infralimbic cortex, caudate putamen, nucleus accumbens core, bed nucleus of stria terminalis, hipothalamic paraventricular nucleus, medial amygdaloid nucleus, lateral habenula, substantia nigra pars compacta and pars reticulata, ventral tegmental area, hippocampal ventral subiculum, dorsal and ventral periaqueductal gray matters, and medial entorhinal cortex. These findings suggest that the stimulation of the lateral entorhinal cortex and hippocampal dorsal subiculum play a role in therapeutic effects of antidepressants.

Increased Fear Memory and Glutamatergic Modulation in Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia.

Compulsive behavior is observed in several neuropsychiatric disorders such as obsessive-compulsive disorder (OCD), anxiety, depression, phobia, and schizophrenia. Thus, compulsivity has been proposed as a transdiagnostic symptom with a highly variable pharmacological treatment. Recent evidence shows that glutamate pharmacotherapy may be of benefit in impaired inhibitory control. The purpose of the present study was: first, to test the comorbidity between compulsivity and other neuropsychiatric symptoms on different preclinical behavioral models; second, to assess the therapeutic potential of different glutamate modulators in a preclinical model of compulsivity. Long Evans rats were selected as either high (HD) or low (LD) drinkers corresponding with their water intake in schedule-induced polydipsia (SIP). We assessed compulsivity in LD and HD rats by marble burying test (MBT), depression by forced swimming test (FST), anxiety by elevated plus maze (EPM) and fear behavior by fear conditioning (FC) test. After that, we measured the effects of acute administration (i.p.) of glutamatergic drugs: N-Acetylcysteine (NAC; 25, 50, 100 and 200 mg/kg), memantine (3.1 and 6.2 mg/kg) and lamotrigine (15 and 30 mg/kg) on compulsive drinking on SIP. The results obtained showed a relation between high compulsive drinking on SIP and a higher number of marbles partially buried in MBT, as well as a higher percentage of freezing on the retrieval day of FC test. We did not detect any significant differences between LD and HD rats in FST, nor in EPM. The psychopharmacological study of glutamatergic drugs revealed that memantine and lamotrigine, at all doses tested, decreased compulsive water consumption in HD rats compared to LD rats on SIP. NAC did not produce any significant effect on SIP. These results indicate that the symptom clusters of different forms of compulsivity and phobia might be found in the compulsive phenotype of HD rats selected by SIP. The effects of memantine and lamotrigine in HD rats point towards a dysregulation in the glutamatergic signaling as a possible underlying mechanism in the vulnerability to compulsive behavior on SIP. Further studies on SIP, could help to elucidate the therapeutic role of glutamatergic drugs as a pharmacological strategy on compulsive spectrum disorders.

Upregulation of hippocampal extracellular signal-regulated kinase (ERK)-2 induces antidepressant-like behavior in the rat forced swim test.

The hippocampus mediates responses to affect-related behavior in preclinical models of pharmacological antidepressant efficacy, such as the forced swim test. However, the molecular mechanisms that regulate escape-directed behavior in this preclinical model of despair are not well understood. Here, using viral-mediated gene transfer, we assessed how overexpression of extracellular signal-regulated protein kinase (ERK)-2 within the dorsal hippocampus influenced behavioral reactivity to inescapable swimming stress in adult male Sprague-Dawley rats. When compared to controls, rats overexpressing hippocampal ERK-2 displayed increases in the time to initially adopt a posture of immobility, along with decreases in total time spent immobile, without influencing general locomotor activity. Collectively, the results indicate that hippocampal upregulation of ERK-2 increases escape-directed behavior in the rat forced swim test, thus providing insight into the neurobiological mechanisms that mediate antidepressant efficacy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Atropine counteracts the depressive-like behaviour elicited by acute exposure to commercial chlorpyrifos in rats

Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24 h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30 days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10 mg/kg i.p.) and/or pralidoxime (40 mg/kg; i.p.) given 1 h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats.

Novel antagonists of 5-HT6 and/or 5-HT7 receptors affect the brain monoamines metabolism and enhance the anti-immobility activity of different antidepressants in rats

The aim of the present study was to investigate and compare the ability of three novel 5-HT6 and/or 5-HT7 receptor antagonists as follows: PZ-668—a preferential 5-HT6 antagonist; PZ-1433—a preferential 5-HT7 antagonist; and ADN-1184—a monoaminergic ligand with potent 5HT6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments. The results of our investigations revealed the differences in action of the tested compounds. PZ-668 strongly affected dopaminergic and faintly noradrenergic system, PZ-1433 induced a significant elevation in dopamine, noradrenaline, serotonin, and their metabolite levels, while ADN-1184 appeared to act mostly through dopaminergic transmission. The agent with 5-HT6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT7 preferential antagonist facilitated antidepressant effects of escitalopram and, to a lesser extent, bupropion, while ADN-1184, a multireceptor ligand, potentiated the effectiveness of escitalopram, reboxetine, and bupropion. The presented findings may contribute to further investigations of more effective and safer antidepressant drugs, and may help selecting optimal augmentation therapy in treatment-resistant depression.

Kappa opioid regulation of depressive-like behavior during acute withdrawal and protracted abstinence from ethanol.

The dynorphin/kappa opioid receptor (DYN/KOR) system appears to be a key mediator of the behavioral effects of chronic exposure to alcohol. Although KOR opioid receptor antagonists have been shown to decrease stress-related behaviors in animal models during acute ethanol withdrawal, the role of the DYN/KOR system in regulating long-term behavioral changes following protracted abstinence from ethanol is not well understood. The objective of the current study was to further explore the role of the DYN/KOR system in regulating stress-related behavioral changes associated with acute withdrawal and protracted abstinence from ethanol. More specifically, the present experiments sought to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to reverse depressive-like behavior in the forced swim test in rats exposed to chronic ethanol. In the first experiment, rats were fed an ethanol or control liquid diet for 28–30 days, and then 24 hours after removal of the diet, were exposed to inescapable swim stress. Immediately following this procedure, rats were injected with nor-BNI (20 mg/kg) or saline and then tested 24 hours later in the forced swim test. A second experiment used a similar procedure to examine the effects of nor-BNI on behavioral changes during protracted abstinence in rats tested in the forced swim test 3 weeks after exposure to the ethanol liquid diet procedure. Ethanol-dependent rats showed increased immobility, which is thought to indicate a depressive-like state, when examined during acute withdrawal and protracted abstinence compared to controls, an effect attenuated by nor-BNI. These results suggest that the DYN/KOR system plays role in mediating both short- and long-term behavioral changes associated with depression following chronic alcohol exposure.

Prenatal Effect of Fluoxetine on Nociceptive System Reactivity and Psychoemotional Behavior of Young Female and Male Rats

Reactivity of the nociceptive system, psychoemotional behavior and cognitive abilities in female and male rats born to mothers that were exposed to chronic injection of fluoxetine, a serotonin reuptake inhibitor, on days 9–20 of pregnancy were studied in a battery of behavioral tests during the prepubertal period. It was found that chronic injection of physiological saline to pregnant females evoked enhanced nociceptive responses in their offspring of both sexes while fluoxetine injection neutralized the effects of such an invasive intervention, demonstrating thereby the antinociceptive effect of this agent. Negative effects of maternal fluoxetine included a weight loss in the neonate offspring of both sexes and 25-day-old males, as well as the increased anxiety level in females only as detected in the elevated plus maze test. Fluoxetine had no effect on the level of depressive-like behavior in the forced swim test in rats of both sexes. The positive prenatal effect of fluoxetine manifested itself in males as an improved spatial learning ability in the Morris water maze; the anti-nociceptive effect of chronic fluoxetine injection, as compared to the pro-nociceptive effect of chronic saline injection, can also be considered as a positive effect of fluoxetine. Sex differences in the prenatal effect of fluoxetine were revealed in the anxiety level with more anxiety behavior in females.

The Hippocampus is a Critical Site Mediating Antidepressant-like Activity of Apelin-13 in Rats

The peptide apelin and its receptor APJ are found to express in multiple brain regions, especially in the regions such as the hippocampus and hypothalamus that play important roles in stress and depression. The distribution of apelin and APJ suggests that the apelinergic signaling may be a key mediator in the development of stress-related depressive behavior. We recently demonstrated that intracerebroventricular (i.c.v) injection of apelin-13 exerts an antidepressant-like activity in the rat forced swimming test (FST). However, the possible brain region mediating apelin-13’s antidepressant-like activity remains unclear. In the present study, we determined whether the hippocampus and hypothalamus are the possible regions mediating antidepressant-like activity of apelin-13. We found that forced swimming exposure upregulated apelin and APJ protein expression levels in the hippocampus but not hypothalamus in rats. Further, intrahippocampal injection of apelin-13 exerted an antidepressant-like activity (as indicated by a decreased immobility behavior), and intrahippocampal infusion of APJ receptor antagonist F13A blocked the antidepressant-like activity produced by i.c.v injection of apelin-13 in the FST. Moreover, intrahypothalamic injection of apelin-13 did not affect the immobility behavior in the FST. These findings suggest that the hippocampus, but not hypothalamus, is a critical site mediating antidepressant-like activity of apelin-13 in rats.

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

Study on the effect of EMD386088, a 5-HT6 receptor partial agonist, in enhancing the anti-immobility action of some antidepressants in rats

The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg). Pharmacokinetic in vivo investigation showed a rapid absorption of EMD386088 (2.5 and 5 mg/kg) with t1/2 = 67 min (tmax = 5 min). Large volume of distribution (Vd/F = 102 L/kg) indicated its penetration into peripheral compartments. The most active coadministration of EMD386088 (2.5 mg/kg) with imipramine (15 mg/kg) resulted in slower absorption of the compound (Cmax = 60 min) and decrease in the volume of distribution (Vd/F = 32.2 L/kg). EMD386088 penetrates the blood–brain barrier with a high brain/plasma ratio of about 19 (2.5 mg/kg) and 7.5 for coadministration with imipramine. The in silico and in vitro studies on EMD386088 metabolic stability showed the dehydrogenation of tetrahydropyridine moiety as its main metabolic pathway. EMD386088 did not influence on CYP3A4 activity, and it has been classified as a very weak CYP2D6 inhibitor (IC50 = 2.25 μM). The results obtained from the forced swim test in rats indicate that an activation of 5HT6 receptor may facilitate antidepressant-like activity of some antidepressants. The pharmacokinetic results suggest that the interaction between EMD386088 and imipramine could not have been pharmacokinetic in nature.

Assessment of Chaenomeles maulei fruit juice effects in the forced swim test in rats

Assessment of Chaenomeles maulei fruit juice effects in the forced swim test in rats

P.2.e.005 - Time-course antidepressant-like effect of repeated electroconvulsive shock as measured by the time spent immobile in the forced-swim test in rats

Comminuted fractures of the proximal ulna remain a great challenge in orthopedic surgery. The purpose of this study was to report the outcomes of comminuted proximal ulna fractures treated with a new construct type—anatomically preformed polyaxial locking compression plates.Between 2013 and 2016, 46 patients with isolated comminuted fractures were treated with a 2.7-/3.5-mm VA-LCP Olecranon Plate (Synthes, Umkirch, Germany). Of these, 44 were available for an assessment after a mean follow-up period of 2.5 years (range, 12-50 months). We evaluated range of motion, time to recovery, revision rate, and indications, as well as functional scores. Radiographs were analyzed.The study included 8 Mayo IB, 29 Mayo IIB, and 7 Mayo IIIB fractures. All fractures showed bony union, and only 2 revision surgical procedures were performed because of a new trauma. No other complications occurred. Mean range of motion was 139° (range, 105°-150°), and the mean pain level was less than 1 on a visual analog scale. Regarding elbow function, we found a mean Mayo Elbow Performance Score of 98; a mean Oxford Elbow Score of 44; and a mean Disabilities of the Arm, Shoulder and Hand score of 6. Of the plates, 41% were removed after an average time of 16 months, whereby a significant improvement in extension deficit was detected (P < .01). Ninety-five percent of all patients returned to their pretrauma sports level.The 2.7-/3.5-mm VA-LCP Olecranon Plate represents an effective option with excellent fracture reduction, sufficient stability for early postoperative functional rehabilitation, and a minimum of complications.

Dopamine and serotonin contribute to Paecilomyceshepiali against chronic unpredictable mild stress induced depressive behavior in Sprague Dawley rats.

Paecilomyces hepiali contains identical chemical constituents to Cordycepssinensis, and it presents antidepressant‑like activity via regulating noradrenergic and dopaminergic systems. Behavioral despair depression models serve important roles in scientific screening and evaluation of antidepressants. The present study aims to investigate the antidepressant‑like activity of P. hepiali extract (PHC) in chronic unpredictable mild stress (CUMS)‑induced rat model of depression. Following four weeks of treatment, similar to fluoxetine at 3mg/kg (positive drug), PHC at doses from 0.08 to 2.0g/kg strongly increased sucrose preference and reduced the immobility time of depression‑like rats in forced swimming test. The hypo‑level of adrenocorticotropic hormone, noradrenaline and glucocorticoid receptor in serum and hypothalamus of depression‑like rats was enhanced by PHC. PHC normalized CUMS‑induced disorders of dihydroxyphenylacetic acid, dopamine, 5‑hydroxytryptamine (5‑HT) and 5‑hydroxyindoleacetic acid in serum and/or hypothalamus of depression‑like rats. Moreover, PHC enhanced the expression of tyrosine hydroxylase and reduced the levels of dopamine D2 receptor and 5‑HT2A receptor in hypothalamus. These results suggested that the antidepressant‑like effects of PHC in CUMS‑induced depression are associated with not only the modulation of dopamine, but also the regulation of 5-HT.

Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3mg/kg, q.d.).

Involvement of extracellular signal-regulated kinase (ERK) in the short and long-lasting antidepressant-like activity of NMDA receptor antagonists (zinc and Ro 25-6981) in the forced swim test in rats

Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear. More puzzling is the fact that the precise role of ERK in the short and long lasting effects of long-acting NMDAR antagonists is unknown. In this study, we show that zinc, (Zn) a short-acting NMDAR antagonist evokes only transient ERK activation, which is observed 7 min after its administration in the PFC of rats. In contrast to Zn, the long acting NMDAR antagonist Ro 25-6981 produces persistent ERK activation lasting up to 24 h. Pretreatment with the MAPK/ERK inhibitor (U0126) totally abolished Zn and Ro 25-6981 antidepressant-like activities in the forced swim test in rats. However, when U0126 is administered 15 min after Zn or Ro 25-6981 both compounds maintain their short-lasting antidepressant-like activity. On the other hand, posttreatment with U0126 significantly attenuated the long lasting antidepressant-like activity of Ro 25-6981. These results indicate that the activation of ERK is crucial for the short- and long lasting antidepressant-like activity observed in the FST in rats.

Inhibition of the CRF1 receptor influences the activity of antidepressant drugs in the forced swim test in rats

Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and impairment of the central corticotropin-releasing factor (CRF) system are factors in the pathogenesis of depression. Though several antagonists of the CRF1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between CRF1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of SN003, a CRF1 receptor blocker, on the activity of imipramine and fluoxetine in the forced swim test (FST) in rats which presented some signs of depression. The experiments were carried out on female Wistar rats subjected to 14-day subcutaneous corticosterone (CORT) administration (20 mg/kg/day). The antidepressant-like effect was determined by the FST and the CRF levels in the hypothalamus, amygdala, and peripheral blood were measured by a high-sensitivity immunoenzymatic test. SN003 (0.5 mg/kg) potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (7.5 mg/kg). Moreover, the co-administration of the tested agents abolished CORT-induced increase in CRF levels in the examined biological material more profoundly than monotherapy. Our present findings give further evidence that the blockage of CRF action may be useful in the treatment of mood disorders. The concurrent use of well-known antidepressants with CRF1 receptor antagonists could be beneficial in terms of safety, since it requires lower doses of the applied agents.

The computer-aided discovery of novel family of the 5-HT6 serotonin receptor ligands among derivatives of 4-benzyl-1,3,5-triazine

The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2, weakly active for the H4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT6R ligand, occurred to be a moderate 5-HT6R agent, useful as a lead structure for further modifications. A series of new derivatives (3–19) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure-based approaches with docking to the homology model of 5-HT6R. The most active compounds displayed a potent affinity for the 5-HT6R in the nanomolar range (Ki = 20–30 nM), some of them (4, 11 and 19) were tested in the rat forced swim test that revealed their antidepressant-like effect. SAR-analysis on the basis of both, RBA and docking results, indicated that action on the receptor is related to the hydrophobicity and the size of aromatic moiety substituted by a methylene linker at the position 4 of 1,3,5-triazine.

Participation of hippocampal nitric oxide synthase and soluble guanylate cyclase in the modulation of behavioral responses elicited by the rat forced swimming test.

Systemic or hippocampal administration of nitric oxide (NO) synthase inhibitors induces antidepressant-like effects in animals, implicating increased hippocampal levels of NO in the neurobiology of depression. However, the role played by different NO synthase in this process has not been clearly defined. As stress is able to induce neuroinflammatory mechanisms and trigger the expression of inducible nitric oxide synthase (iNOS) in the brain, as well as upregulate neuronal nitric oxide synthase (nNOS) activity, the aim of the present study was to investigate the possible differential contribution of hippocampal iNOS and nNOS in the modulation of the consequences of stress elicited by the forced swimming test. Male Wistar rats received intrahippocampal injections, immediately after the pretest or 1 h before the forced swimming test, of selective inhibitors of nNOS (N-propyl-L-arginine), iNOS (1400W), or sGC (ODQ), the main pharmacological target for NO. Stress exposure increased nNOS and phospho-nNOS levels at all time points, whereas iNOS expression was increased only 24 h after the pretest. All drugs induced an antidepressant-like effect. However, whereas the nNOS inhibitor was equally effective when injected at different times, the iNOS inhibitor was more effective 24 h after the pretest. These results suggest that hippocampal nNOS and iNOS contribute to increase in NO levels in response to stress, although with a differential time course after stress exposure.

The effect of montelukast on depression behaviour in rat forced swimming test

Objective: Montelukast (brand name: Singulair), which is used for treatment of chronic asthma, is a leukotriene receptor antagonist. The psychiatric side effects of montelukast use in asthma patients are controversial. The aim of this study is to examine the effect of montelukast treatment on depression behavior in both healthy and asthmatic rats. Method: 50 wistar albino female rats, of between 150 and 250 g in weight, were used in this study. The study was conducted with two groups: Group I: healthy group; including control, asthma, and montelukast-treated asthma subgroups (n=20) and Group II: asthmatic group including control, asthma, and montelukast-treated asthma subgroups (n=30). The bronchial asthma model was employed for all the rats in the asthmatic group. In this model, the animals were sensitized by giving ovalbumin intraperitoneally and they were also provoked by breathing ovalbumin. Montelukast was given to the rats intraperitoneally at a dose of 10 mg/kg for 10 days in montelukast-treated subgroups of both groups. A forced swimming test was used to determine the effect of montelukast treatment on depression behavior. Results: In the healthy rats (Group I), immobility time increased in montelukast-treated asthmatic rats compared to the control subgroup (p0.05). However, in this group (Group II), immobility time was higher in montelukast-treated asthmatic rats compared to saline treated asthmatic rats (p

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

RationaleIt has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model.ObjectiveIn the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression.ResultsWe observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810.ConclusionOur results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.