Impacts of maternal separation stress on ethanol-related responses, anxiety- and depressive-like behaviors in adolescent mice.

The present work evaluated the consequences of chronic maternal separation (MS), an animal model of early-life stress, on ethanol intake and striatal Fos expression induced by ethanol consumption. Furthermore, we analyzed MS impacts on anxiety- and depressive-like behaviors and on locomotor and plasma corticosterone responses to intraperitoneal treatment with ethanol in adolescent mice. For that, male and female C57BL/6J mice were exposed or not to MS stress, for 3 h per day, from postnatal day (PND) 1 to 14, and submitted to behavioral tests from PND 28. In Experiment 1, MS and control groups of mice were submitted to an involuntary ethanol intake protocol, and striatal Fos expression following ethanol exposure was analyzed. In Experiment 2, mice behavior was assessed in elevated plus-maze, sucrose splash, saccharin preference, and open field tests. Locomotor and plasma corticosterone responses induced by a systemic dose of ethanol (1.75 g/kg) were also evaluated. Our results demonstrated that MS increased ethanol intake only in an acute manner and did not impact ethanol-induced Fos expression in the dorsal striatum and nucleus accumbens (NAc) core and shell subregions. MS did not change the parameters analyzed during elevated plus-maze, sucrose splash, preference for saccharin, and open field tests. MS did not affect locomotor activity following ethanol injection nor plasma corticosterone response to the drug. Thus, our data showed that MS transiently increased ethanol intake. However, early-life stress did not impact Fos, locomotor, or plasma corticosterone responses to the drug. In addition, MS did not affect anxiety- and depressive-like behaviors in adolescent mice.

Limited bedding nesting paradigm alters maternal behavior and pup's early developmental milestones but did not induce anxiety- or depressive-like behavior in two different inbred mice.

Animal models are crucial to understanding the mechanisms underlying the deleterious consequences of early-life stress. Here, we aimed to examine the effect of the limited bedding nesting (LBN) paradigm on early life development milestones and anxiety- and/or depression-like behavior in adolescent and adult mice from two inbred mice of both sexes. C57BL/6NCrl and BALB/c litters were exposed to the LBN paradigm postnatal day (PND) 2-9. Maternal behavior recording occurred on PND 3-9, and pups were weighed daily and examined to verify the eye-opening on PND 10-22. The male and female offspring underwent evaluation in the open field test, elevated plus-maze, and the forced swimming test during adolescence (PND 45-49) and adulthood (PND 75-79). We found that LBN impaired the maternal behavior patterns of both strain dams, mainly on C57BL/6NCrl strain. Also, LBN delayed the pup's eye-opening time and reduced body weight gain, impacting C57BL/6NCrl pups more. We also found that LBN decreased anxiety-related indices in adolescent and adult male but not female mice of both strains. Furthermore, LBN decreased depression-related indices only adolescent female and male BALB/c and female but not male C57BL/6NCrl mice. These findings reinforce the evidence that the LBN paradigm impairs the maternal behavior pattern and pup's early developmental milestones but does not induce anxiety- or depressive-like behavior outcomes during later life.

Involvement of kynurenine pathway and N-methyl-d-aspartate receptors in the antidepressant-like effect of vilazodone in the tail suspension test in mice.

The present study evaluated the antidepressant-like effects of vilazodone using the tail suspension test in mice. We also investigated the contribution of kynurenine pathway and N-methyl-d-aspartate receptors to this effect. For this purpose, we pretreated animals with sub-effective doses of L-kynurenine, 3-hydroxykynurenine, or quinolinic acid. We then assessed the immobility time, an indicative measure of depressive-like behavior, in the tail suspension test. We also evaluated the possible effects of sub-effective doses of vilazodone combined with sub-effective doses of ketamine (N-methyl-d-aspartate receptor antagonist) in a separate group. Vilazodone (3mg/kg, intraperitoneal) significantly reduced immobility time in the tail suspension test. L-kynurenine (1.7 mg/kg, intraperitoneal), 3-hydroxykynurenine (10 mg/kg, intraperitoneal), and quinolinic acid (3 nmol/site, intracerebroventricular) significantly increased the immobility time in the tail suspension test. The antidepressant-like effects of vilazodone (3mg/kg, intraperitoneal) were inhibited by pre-treatment with non-effective doses of L-kynurenine (0.83 mg/kg, intraperitoneal), 3-hydroxykynurenine (3.33 mg/kg, intraperitoneal), or quinolinic acid (1 nmol/site, intracerebroventricular). Pretreatment of mice with sub-effective doses of ketamine (1 mg/kg, intraperitoneal) optimized the action of a sub-effective dose of vilazodone (0.3mg/kg, intraperitoneal) and reduced the immobility time in the tail suspension test. None of the drugs used in this study induced any changes in locomotor activity in the open field test. The results showed that vilazodone induced an antidepressant-like effect in the tail suspension test, which may be mediated through an interaction with the kynurenine pathway and N-methyl-d-aspartate receptors.

High-Fat Diet and Short-Term Unpredictable Stress Increase Long-Chain Ceramides Without Enhancing Behavioral Despair.

Clinical and preclinical studies suggest that increases in long-chain ceramides in blood may contribute to the development of depressive-like behavior. However, which factors contribute to these increases and whether the increases are sufficient to induce depressive-like behaviors is unclear. To begin to address this issue, we examined the effects of high fat diet (HFD) and short-term unpredictable (STU) stress on long-chain ceramides in the serum of male and female rats. We found that brief exposure to HFD or unpredictable stress was sufficient to induce selective increases in the serum concentrations of long-chain ceramides, associated with depression in people. Furthermore, combined exposure to HFD and unpredictable stress caused a synergistic increase in C16:0, C16:1, and C18:0 ceramides in both sexes and C18:1 and C24:1 in males. However, the increased peripheral long-chain ceramides were not associated with increases in depressive-like behaviors suggesting that increases in serum long-chain ceramides may not be associated with the development of depressive-like behaviors in rodents.

Coadministration of tianeptine alters behavioral parameters and levels of neurotrophins in a chronic model of Maple Syrup Urine disease.

Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.

Toxicological evaluation of ethanolic extract of leaves from Doliocarpus dentatus in Swiss mice.

Doliocarpus dentatus (Dilleniaceae) has been used in folk medicine to treat inflammation and pain; however, studies evaluating its toxicity potential, as well as its effects on anxiety and depression, are scarce. This study investigated the toxicological profile of an ethanolic extract from leaves of D. dentatus (EEDd), and its effects on anxiety and depression models in mice. Male and female mice received either a single dose (500, 1000 or 2000 mg/kg) or repeated doses (75, 150 or 300 mg/kg) of EEDd by oral gavage. During the subacute toxicity assay, behavioral tests were performed on days 4, 14, 21 and 28. No evidence of toxicity was observed in the animals in both acute and subacute tests. However, males treated with the highest dose presented a reduction in the absolute weight of the kidney, an elevation in the AST levels, in addition to an alteration in the urea levels. The treatment did not affect other biochemical parameters, and did not induce any depressive-like behavior. EEDd exhibited low toxicity after single and repeated exposures. Since some analyzed parameters were compromised, further toxicity studies should be carried out.

Chronic unpredictable restraint stress increases hippocampal pro-inflammatory cytokines and decreases motivated behavior in rats.

Most chronic stress protocols are too laborious or do not abide by the two main characteristics of the stress concept: uncontrollability and unpredictability. The goal of this study was to establish a simple and reliable model of chronic stress, while maintaining the main features of the concept. Animals were exposed to chronic movement restraint with variable duration (2, 4 or 6 h, in an unpredictable schedule) for 3 weeks and assessed in several physiological and behavioral readouts known to reflect chronic stress states. Body weight, levels of plasma corticosterone, hippocampal pro-and anti-inflammatory cytokines, anxiety-like (novelty suppressed feeding and elevated plus maze) and motivated behaviors (sucrose negative contrast test and forced swim test) were evaluated three days after the end of the chronic protocol. Stressed animals had a lower body weight gain, higher levels of cytokines in the hippocampus, reduced suppression of a low concentration sucrose solution and increased immobility in the forced swim test. Based on these data, we suggest that chronic movement restraint with variable duration may be a suitable and simple protocol for the study of changes induced by chronic stress and for the testing of possible treatments relevant to psychiatry.

Depression comorbidity in epileptic rats is related to brain glucose hypometabolism and hypersynchronicity in the metabolic network architecture.

OBJECTIVE: Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy syndromes in the world. Depression is an important comorbidity of epilepsy, which has been reported in patients with TLE and in different experimental models of epilepsy. However, there is no established consensus on which brain regions are associated with the manifestation of depression in epilepsy. Here, we investigated the alterations in cerebral glucose metabolism and the metabolic network in the pilocarpine-induced rat model of epilepsy and correlated it with depressive behavior during the chronic phase of epilepsy. METHODS: Fluorodeoxyglucose (18 F-FDG) was used to investigate the cerebral metabolism, and a cross-correlation matrix was used to examine the metabolic network in chronically epileptic rats using micro-positron emission tomography (microPET) imaging. An experimental model of epilepsy was induced by pilocarpine injection (320 mg/kg, ip). Forced swim test (FST), sucrose preference test (SPT), and eating-related depression test (ERDT) were used to evaluate depression-like behavior. RESULTS: Our results show an association between epilepsy and depression comorbidity based on changes in both cerebral glucose metabolism and the functional metabolic network. In addition, we have identified a significant correlation between brain glucose hypometabolism and depressive-like behavior in chronically epileptic rats. Furthermore, we found that the epileptic depressed group presents a hypersynchronous brain metabolic network in relation to the epileptic nondepressed group. SIGNIFICANCE: This study revealed relevant alterations in glucose metabolism and the metabolic network among the brain regions of interest for both epilepsy and depression pathologies. Thus it seems that depression in epileptic animals is associated with a more diffuse hypometabolism and altered metabolic network architecture and plays an important role in chronic epilepsy.

Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress.

We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[14C]-glutamate uptake and increased 45Ca2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring.

Activation of Brain Indoleamine-2,3-dioxygenase Contributes to Depressive-Like Behavior Induced by an Intracerebroventricular Injection of Streptozotocin in Mice.

There is a lack of information concerning the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. The elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In the present study, we reported that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, as measured by the increased duration of immobility in the tail suspension test and decreased sucrose intake in the sucrose preference test. The blockade of IDO activation by the IDO inhibitor 1-methyltryptophan (1-MT) prevents the development of depressive-like behaviors and attenuates STZ-induced up-regulation of proinflammatory cytokines in the hippocampus. 1-MT abrogates kynurenine production and normalizes brain-derived neurotrophic factor (BDNF) and the kynurenine/tryptophan ratio, but does not protect the biomarkers of the serotonin (5-HT) system in the hippocampus of STZ-injected mice. These results implicate IDO as a critical molecular mediator of STZ-induced depressive-like behavior, likely through activation of the kynurenine pathway and subsequent reduction of BDNF levels. Impairment of the 5-HT system may reflect the inflammatory response induced by STZ and also contributes to observed depression symptoms. The present study not only provides evidence that IDO plays a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets for novel therapeutic drugs for depression. In addition, this study provides new insights on the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in preclinical research of depression.

Intracerebroventricular Administration of Streptozotocin as an Experimental Approach to Depression: Evidence for the Involvement of Proinflammatory Cytokines and Indoleamine-2,3-Dioxygenase.

There is a lack of information about the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. Elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In this study, we report that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, measured by an increased duration in immobility time in the forced swimming test and decreased total time of grooming in the splash test. Indirect blockade of IDO activation with the cytokine inhibitor minocycline prevents the development of depressive-like behaviors and attenuates STZ-induced upregulation of proinflammatory cytokines in the hippocampus. Minocycline abrogates the increase in tryptophan and kynurenine levels as well as prevents serotonin dysfunction in the hippocampus of STZ-injected mice. These results suggest that hippocampal IDO activation in STZ-associated depressive-like behavior is mediated by proinflammatory cytokine-dependent mechanisms. Our study not only extends the evidence that IDO has a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets of novel therapeutic drugs for depression. In addition, our study provides new insights into the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in the preclinical research of depression.

A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria.

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.

Depression-Like Adult Behaviors may be a Long-Term Result of Experimental Pneumococcal Meningitis in Wistar Rats Infants.

Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS) with a high mortality rate. In addition to causing severe neurological sequelae infectious diseases of the CNS can play a significant role in the pathogenesis of neuropsychiatric disorders. In this study infant Wistar rats, postnatal day 11, received intracerebroventricular (i.c.v.) either artificial cerebrospinal fluid (CSF) or a Streptococcus pneumoniae suspension to a concentration of 1 × 106 colony-forming units (CFU). 18 h later animals received antibiotic treatment as usual during 7 days. On postnatal day 46, the animals received imipramine intraperitoneal (i.p.) or sterile NaCl during 14 days (postnatal days 46-60). Then, on postnatal days 59-60 we evaluated the consumption of sweet food (an index of anhedonia). On postnatal day 60 the animals were submitted to the forced swimming task. 60 min after this task the animals were decapitated and the blood was collected to evaluate adrenocorticotropic hormone (ACTH) and corticosterone. Immediately after blood collection the hippocampus was removed to evaluate brain-derived neurotropic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The meningitis group exhibited depressive-like behavior as evidenced by decreased sucrose intake and increased immobility time in the forced swimming task, and BDNF and GDNF decrease in the hippocampus. ACTH levels were increased in the blood. Imipramine treatment reversed depressive-like behaviors, re-established hippocampal BDNF and GDNF expression, and normalized ACTH levels in the blood. Here we demonstrate that meningitis during early life period can trigger depressive-like behavior in adult life of rats.

Diphenyl diselenide elicits antidepressant-like activity in rats exposed to monosodium glutamate: A contribution of serotonin uptake and Na(+), K(+)-ATPase activity.

Depression is a disorder with symptoms manifested at the psychological, behavioral and physiological levels. Monosodium glutamate (MSG) is the most widely used additive in the food industry; however, some adverse effects induced by this additive have been demonstrated in experimental animals and humans, including functional and behavioral alterations. The aim of this study was to investigate the possible antidepressant-like effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, in the depressive-like behavior induced by MSG in rats. Male and female newborn Wistar rats were divided in control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4g/kg/day) from the 1st to 5th postnatal day. At 60th day of life, animals received (PhSe)2 (10mg/kg, intragastrically) 25min before spontaneous locomotor and forced swimming tests (FST). The cerebral cortices of rats were removed to determine [(3)H] serotonin (5-HT) uptake and Na(+), K(+)-ATPase activity. A single administration of (PhSe)2 was effective against locomotor hyperactivity caused by MSG in rats. (PhSe)2 treatment protected against the increase in the immobility time and a decrease in the latency for the first episode of immobility in the FST induced by MSG. Furthermore, (PhSe)2 reduced the [(3)H] 5-HT uptake and restored Na(+), K(+)-ATPase activity altered by MSG. In the present study a single administration of (PhSe)2 elicited an antidepressant-like effect and decrease the synaptosomal [(3)H] 5-HT uptake and an increase in the Na(+), K(+)-ATPase activity in MSG-treated rats.

Object recognition memory deficit and depressive-like behavior caused by chronic ovariectomy can be transitorialy recovered by the acute activation of hippocampal estrogen receptors.

It is well known that estradiol (E2) replacement therapy is effective on restoring memory deficits and mood disorders that may occur during natural menopause or after surgical ovarian removal (ovariectomy, OVX). However, it is still unknown the effectiveness of acute and localized E2 administration on the effects of chronic OVX. Here we tested the hypothesis that the intra-hippocampal E2 infusion, as well as specific agonists of estrogen receptors (ERs) alpha (ERα) and beta (ERß), are able to mend novel object recognition (NOR) memory deficit and depressive-like behavior caused by 12 weeks of OVX. We found that both ERα and ERß activation, at earlier stages of consolidation, recovered the NOR memory deficit caused by 12 w of OVX. Conversely, only the ERß activation was effective in decreasing the depressive-like behavior caused by 12 w of OVX. Furthermore, we investigated the effect of OVX on hippocampal volume and ERs expression. The structural MRI showed no alteration in the hippocampus volume of 12 w OVX animals. Interestingly, ERα expression in the hippocampus decreased after one week of OVX, but increased in 12 w OVX animals. Overall, we may conclude that the chronic estrogen deprivation, induced by 12 weeks of OVX, modulates the hippocampal ERα expression and induces NOR memory deficit and depressive-like behaviors. Nonetheless, it is noteworthy that the acute effects of E2 on NOR memory and depressive-like behavior are still apparent even after 12 weeks of OVX.

Monosodium glutamate, a food additive, induces depressive-like and anxiogenic-like behaviors in young rats.

UNLABELLED: Monosodium glutamate (MSG) has been the target of research due to its toxicological effects. AIMS: We investigated the depressive- and anxiogenic-like behaviors in rats exposed to neonatal subcutaneous injection of MSG. The involvement of the serotonergic system, by measuring [(3)H] serotonin (5-HT) uptake in cerebral cortices, and the hypothalamic pituitary adrenal (HPA) axis, by determining serum adrenocorticotropic hormone (ACTH) and corticosterone levels, was also examined. MATERIALS AND METHODS: Male and female newborn Wistar rats were divided into control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 5th postnatal day. The behavioral tests [spontaneous locomotor activity, contextual fear conditioning, and forced swimming test (FST)] were performed from the 60th to 64th postnatal day. MSG-treated animals showed alteration in the spontaneous locomotor activity, an increase in the number of fecal pellets and the number of animal's vocalizations and urine occurrence, and a decrease in the grooming time. KEY FINDINGS: The MSG exposure increased the immobility time in the FST and the freezing reaction in the contextual fear conditioning. Additionally, MSG treatment increased the [(3)H]5-HT uptake in the cerebral cortices of rats and induced a deregulation of HPA axis function (by increasing serum ACTH and corticosterone levels). SIGNIFICANCE: In conclusion MSG-treated rats are more susceptible to develop anxiogenic- and depressive-like behaviors, which could be related to a dysfunction in the serotonergic system.

Antidepressant-like effect of nitric oxide synthase inhibitors and sildenafil against lipopolysaccharide-induced depressive-like behavior in mice.

Inflammation, oxidative and nitrosative stress underlie depression being assessed in rodents by the systemic administration of lipopolysacharide (LPS). There is an increasing body of evidence of an involvement of nitric oxide (NO) pathway in depression, but this issue was not investigated in LPS-induced model. Thus, herein we evaluated the effects of NO-pathway-modulating drugs, named aminoguanidine, l-NAME, sildenafil and l-arginine, on the behavioral (forced swimming test [FST], sucrose preference [SPT] and prepulse inhibition [PPI] of the startle) and neurochemical (glutathione [GSH], lipid peroxidation, IL-1ß) alterations in the prefrontal cortex, hippocampus and striatum as well as in BDNF levels in the hippocampus 24h after LPS (0.5mg/kg, i.p.) administration, a time-point related to depressive-like behavior. Twenty-four hours post LPS there was an increase in immobility time in the FST, decrease in sucrose preference and PPI levels accompanied by a decrease in GSH levels and an increase in lipid peroxidation, IL-1ß and hippocampal BDNF levels suggestive of a depressive-like state. The pretreatment with the NOS inhibitors, l-NAME and aminoguanidine as well as sildenafil prevented the behavioral and neurochemical alterations induced by LPS, although sildenafil and l-NAME were not able to prevent the increase in hippocampal BDNF levels induced by LPS. The iNOS inhibitor, aminoguanidine, and imipramine prevented all behavioral and neurochemical alterations induced by LPS. l-arginine did not prevent the alterations in immobility time, sucrose preference and GSH induced by LPS. Taken together our results show that the NO-cGMP pathway is important in the modulation of the depressive-like alterations induced by LPS.

Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin.

Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40-70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with "emotional" impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions.

Diphenyl diselenide supplemented diet reduces depressive-like behavior in hypothyroid female rats.

Hypothyroidism has been associated to psychiatric disorder development and tissue oxidative damage. In this study, we evaluated the effect of diphenyl diselenide supplementation on depressive-like behavior triggered by methimazole exposure in female rats. Additionally, thiobarbituric acid reactive substances (TBARS), reactive oxygen species (ROS) and non-protein thiol (NP-SH) levels were analyzed in cerebral cortex, hippocampus and striatum structures of rats. Monoamine oxidase (MAO) activity was evaluated in total brain. Firstly, female rats received methimazole (MTZ) 20mg/100ml in the drinking water for 30days and were evaluated in open-field and forced swimming tests (FST). In this set of experiments, the rats exposed to MTZ presented a depressive-like behavior, which was evidenced by a significant increase in the immobility time when compared to control group. Thereafter, MTZ-induced hypothyroid rats received either a standard or a diet containing 5ppm of diphenyl diselenide, and then they were evaluated monthly in open-field and FST tests during 3months. No alteration on the locomotor performance was observed among the groups. The depressive-like behavior of hypothyroid rats was blunted by diphenyl diselenide supplementation during all experimental periods. The levels of thyroid hormones remained low in MTZ exposed groups until the end of experimental period. The MTZ group had an increase in TBARS and ROS levels that were restored by diphenyl diselenide supplementation. NP-SH content of cerebral structures was not modified by MTZ exposure and/or diphenyl diselenide supplementation. Diphenyl diselenide supplementation restored the MAO B activity that was decreased in MTZ group. In summary, our results show that hypothyroidism induced by MTZ methimazole triggers a depressive-like behavior in female rats and that dietary diphenyl diselenide was able to reduce this effect.