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Memory impairment in Alzheimer's disease patients is thought to be associated with the accumulation of amyloid-beta peptides and tau proteins. However, inconsistent reports of cognitive deficits in pre-clinical studies have raised questions about the link between amyloid-beta and cognitive decline. One possible explanation may be that studies reporting memory deficits often involve behavioral assessments that entail a high stress component. In contrast, in tasks without a high stress component transgenic mice do not consistently show declines in memory. The glucocorticoid cascade hypothesis of aging and the vicious cycle of stress framework suggest that stress exacerbates dementia progression by initiating a cycle of hypothalamic-pituitary-adrenal axis activation and subsequent brain deterioration. Using the APPswe/PS1dE9 mouse model of amyloidosis, we assessed whether stressor exposure prior to testing differentially impaired cognitive performance of aged male and female mice. As part of a larger study, mice performed a delayed match-to-position (DMTP) or a 3-choice serialreaction time (3CSRT) task. Unexpectedly, these mice did not exhibit cognitive declines during aging. Therefore, at 73 and 74 weeks of age, we exposed mice to a predator odor or forced swim stressor prior to testing to determine if stress revealed cognitive deficits. We predicted stressor exposure would decrease performance accuracy more robustly in transgenic vs. non-transgenic mice. Acute stressor exposure increased accuracy in the DMTP task, but not in the 3CSRT task. Our data suggest that acute stressor exposure prior to testing does not impair cognitive performance in APPswe/PS1dE9 mice. [ABSTRACT FROM AUTHOR]

Memory impairment in Alzheimer’s disease patients is thought to be associated with the accumulation of amyloid-beta peptides and tau proteins. However, inconsistent reports of cognitive deficits in pre-clinical studies have raised questions about the link between amyloid-beta and cognitive decline. One possible explanation may be that studies reporting memory deficits often involve behavioral assessments that entail a high stress component. In contrast, in tasks without a high stress component transgenic mice do not consistently show declines in memory. The glucocorticoid cascade hypothesis of aging and the vicious cycle of stress framework suggest that stress exacerbates dementia progression by initiating a cycle of hypothalamic-pituitary-adrenal axis activation and subsequent brain deterioration. Using the APPswe/PS1dE9 mouse model of amyloidosis, we assessed whether stressor exposure prior to testing differentially impaired cognitive performance of aged male and female mice. As part of a larger study, mice performed a delayed match-to-position (DMTP) or a 3-choice serial-reaction time (3CSRT) task. Unexpectedly, these mice did not exhibit cognitive declines during aging. Therefore, at 73 and 74 weeks of age, we exposed mice to a predator odor or forced swim stressor prior to testing to determine if stress revealed cognitive deficits. We predicted stressor exposure would decrease performance accuracy more robustly in transgenic vs. non-transgenic mice. Acute stressor exposure increased accuracy in the DMTP task, but not in the 3CSRT task. Our data suggest that acute stressor exposure prior to testing does not impair cognitive performance in APPswe/PS1dE9 mice.

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of (R,S)-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine. In humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure. [ABSTRACT FROM AUTHOR]

Rationale: Obesity is considered one of the major global health problems and increases the risk of several medical complications, such as diabetes and mental illnesses. Objective: The present study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on obesity parameters, behavioral and neurochemical alterations in hypothalamic obese rats. Methods: Male Wistar rats received subcutaneous neonatal injections of monosodium glutamate (MSG, 4g/kg) or saline. After the Lee Index evaluation, rats were divided into groups and treated with 4-PSQ (5 mg/kg, intragastric route) or canola oil once a day (post-natal days (PND) 60→76). Open-field, elevated plus-maze, forced swim task, object recognition/location memory, and stepdown inhibitory avoidance tasks were conducted from PND 66 to 74. On PND 76, rats were euthanized and epididymal fat, blood, cerebral cortex, andhippocampus were removed. Blood biochemical parameters and cortical/hippocampal acetylcholinesterase (AChE) and Na /K -ATPase activities were assessed. Results: MSG increased the Lee Index characterizing the chemically induced hypothalamic obesity model. 4-PSQ reversed the increases of epididymal fat, blood glucose, and triglyceride levels caused by MSG exposure. 4-PSQ attenuated anxiety-like and depression-like behaviors induced by neonatal administrations of MSG. Memory deficits found in MSG-obese rats were reversed by treatment with 4-PSQ. Neurochemical alterations produced by MSG evidenced by stimulation ofNa+/K+-ATPase and AChE activities in the cerebral cortex and hippocampus of rats were normalized by 4-PSQ treatment. Conclusions: In brief, 4-PSQ therapy improved hypothalamic obesity-related parameters, as well as psychiatric symptoms, cognitive impairment, and neurochemical alterations found in obese rats. [ABSTRACT FROM AUTHOR]

Exposure to stress during adolescence is a risk factor for developing several psychiatric disorders, many of which involve prefrontal cortex (PFC) dysfunction. The human PFC and analogous rodent medial prefrontal cortex (mPFC) continue to mature functionally and anatomically during adolescence, and some of these maturational events coincide with pubertal onset. As developing brain regions are more susceptible to the negative effects of stress, this may make puberty especially vulnerable. To test this, we exposed male and female rats to isolation and restraint stress during the onset of puberty or during the post‐pubertal period of adolescence. In young adulthood, both stressed groups and an unstressed control group underwent testing on a battery of tasks to assess emotional and cognitive behaviors, and the volume of the mPFC was quantified postmortem. Factor analysis revealed only subjects stressed peri‐pubertally showed a long‐term deficiency compared to controls in prepulse inhibition. Additionally, both sexes showed volumetric mPFC decreases following adolescent stress, and these losses were most pronounced in females. Our findings suggest that pubertal onset may be a vulnerable window wherein adolescents are most susceptible to the negative consequences of stress exposure. Furthermore, it highlights the importance of accounting for pubertal status when studying adolescents. [ABSTRACT FROM AUTHOR]

Abstract: Pain puts patients at risk for developing psychiatric conditions such as anxiety and depression. Preclinical mouse models of pain-induced affective behavior vary widely in methodology and results, impairing progress towards improved therapeutics. To systematically investigate the effect of long-term inflammatory pain on exploratory behavior and stress coping strategy, we assessed male C57BL/6J mice in the forced swim test (FST), elevated zero maze, and open field test at 4 and 6 weeks postinjection of Complete Freund's Adjuvant, while controlling for testing order and combination. Inflammatory pain did not induce a passive stress coping strategy in the FST and did not reduce exploratory behavior in the elevated zero maze or the open field test. Using systematic correlational analysis and composite behavioral scores, we found no consistent association among measures for mice with or without inflammatory pain. A meta-analysis of similar studies indicated a modest, significant effect of Complete Freund's Adjuvant on exploratory behavior, but not immobility in the FST, and high heterogeneity among effect sizes in all 3 paradigms. Given the urgency for understanding the mechanisms of pain comorbidities and identifying novel therapies, these findings support the reallocation of our limited resources away from such unreliable assays and toward motivated and naturalistic behaviors. Future studies in pain and psychiatric translational research may benefit by considering outcomes beyond binary categorization, quantifying the associations between multiple measured behaviors, and agnostically identifying subtle yet meaningful patterns in behaviors. [ABSTRACT FROM AUTHOR]

Patients with stress-triggered major depression disorders (MDD) can often seek comfort or temporary relief through alcohol consumption, as they may turn to it as a means of self-medication or coping with overwhelming emotions. The use of alcohol as a coping mechanism for stressful events can escalate, fostering a cycle where the temporary relief it provides from depression can deepen into alcohol dependence, exacerbating both conditions. Although, the specific mechanisms involved in stress-triggered alcohol dependence and MDD comorbidities are not well understood, a large body of literature suggests that the serotonin transporter (SERT) plays a critical role in these abnormalities. To further investigate this hypothesis, we used a lentiviral-mediated knockdown approach to examine the role of hippocampal SERT knockdown in social defeat stress-elicited depression like behavior and ethanol-induced place preference (CPP). The results showed that social defeat stress-pro depressant effects were reversed following SERT knockdown demonstrated by increased sucrose preference, shorter latency to feed in the novelty suppressed feeding test, and decreased immobility time in the tail suspension and forced swim tests. Moreover, and most importantly, social stress-induced ethanol-CPP acquisition and reinstatement were significantly reduced following hippocampal SERT knockdown using short hairpin RNA shRNA-expressing lentiviral vectors. Finally, we confirmed that SERT hippocampal mRNA expression correlated with measures of depression- and ethanol-related behaviors by Pearson's correlation analysis. Taken together, our data suggest that hippocampal serotoninergic system is involved in social stress-triggered mood disorders as well as in the acquisition and retrieval of ethanol contextual memory and that blockade of this transporter can decrease ethanol rewarding properties. • We investigated the role of hippocampal SERT in depression- and ethanol-related behaviors. • Hippocampal SERT knockdown decreased social stress-elicited depression-like behavior. • SERT shRNA reversed stress-induced ethanol-CPP acquisition and reinstatement. • Hippocampal SERT mRNA correlated with depression and ethanol-related behaviors. [ABSTRACT FROM AUTHOR]

Adolescence represents a critical period of neurodevelopment, defined by structural and synaptic pruning within the prefrontal cortex. While characteristic of typical development, this structural instability may open a window of vulnerability to developing neuropsychiatric disorders, including depression. Thus, therapeutic interventions that support or expedite neural remodeling in adolescence may be advantageous. Here, we inhibited the neuronally-expressed cytoskeletal regulatory factor Rho-kinase (ROCK), focusing primarily on the clinically-viable ROCK inhibitor fasudil. ROCK inhibition had rapid antidepressant-like effects in adolescent mice, and its efficacy was comparable to ketamine and fluoxetine. It also modified levels of the antidepressant-related signaling factors, tropomyosin/tyrosine receptor kinase B and Akt, as well as the postsynaptic marker PSD-95, in the ventromedial prefrontal cortex (vmPFC). Meanwhile, adolescent-typical dendritic spine pruning on excitatory pyramidal neurons in the vmPFC was expedited. Further, vmPFC-specific shRNA-mediated reduction of ROCK2, the dominant ROCK isoform in the brain, had antidepressant-like consequences. We cautiously suggest that ROCK inhibitors may have therapeutic potential for adolescent-onset depression.

Albizia zygia (DC.) J.F. Macbr. (Leguminosae) has been used to treat mental disorders in traditional African medicine. Nonetheless, there is limited scientific evidence to justify its present use. The aim of this study was to evaluate the antidepressant activity of the hydroethanolic extract of A. zygia roots (AZE) in murine models. AZE was evaluated in the tail suspension test, forced swim test, and the repeated open-space swim test of depression. In order to elucidate the mechanisms of action, the activity of AZE was re-evaluated after treating mice with selective inhibitors of monoamine biosynthesis. The potential of AZE to influence spontaneous locomotion was also examined. AZE (100–1000 mg/kg, p.o.) reduced the immobility time of mice in the tail suspension and forced swim tests (at least p < 0.05). In the repeated open-space swim test, AZE reduced the immobility time (at least p < 0.05) while concomitantly increasing the distance swam by mice (p < 0.01). However, the antidepressant-like activity of AZE was attenuated by α-methyl-para-tyrosine and reserpine (p < 0.0001) but not para-chlorophenylalanine. The results of this study indicate that AZE possesses antidepressant-like properties and support the traditional use of AZE for the treatment of depression. [ABSTRACT FROM AUTHOR]

The present study investigated the sensitivity to stress and diazepam in weaning (21-day old) Wistar rats. A single 15-min session of forced swimming was used to induce anxiety-like behavior. The group that was forced to swim exhibited an increase in anxiety-like behavior in the elevated plus maze (EPM) and open field test (OFT) compared to the non-stressed group. Diazepam (1 h before the tests) reduced anxiety-like behavior in rats forced to swim compared to the vehicle stressed group. The dose-response curve for diazepam indicated that the 0.5 mg kg−1 dose (1 h before the EPM and OFT) was the minimum effective dose in reducing anxiety-like behavior without altering locomotor activity in weaning rats. These results indicate that weaning rats can develop anxiety-like behavior after a brief, single session of stress, and that rats at this age are seemingly more sensitive to diazepam than adult rats, which may be taken into account for clinical applications.

Background: Exposure to stressful aversive situations induces physiological and behavioral changes. Serotonin has been suggested to mediate such changes, as well as adaptation to stressful events. Serotoninergic projections arising from the median raphe nucleus to the dorsal hippocampus have been suggested to promote adaptation to chronic aversive stimuli. Such pathway may involve serotonin type 1a receptor-mediated neurotransmission. However, the serotonin 7 receptor can also be found in the median raphe nucleus and may be involved in mechanisms underlying response to stress.Aims: In this work we sought to investigate if activation of serotonin type 7 receptors would attenuate stress-induced deficits in different animal models of depression.Methods: Male Wistar rats with a guide-cannula aimed to the median raphe nucleus were submitted to restraint or forced swim stress and were tested in an elevated plus maze or forced swim test, respectively, 24 h later. SB 258741 (serotonin type 7 receptor antagonist) and/or LP 44 (serotonin type 7 receptor agonist) were administered intra-median raphe nucleus immediately before or after exposure to stress or before test. Control groups received intra-median raphe nucleus treatment 24 h or immediately before test in the elevated plus maze or forced swim test.Results: LP 44 attenuated restraint-induced exploratory deficits independently of the moment it was administered. Similar results were observed in the forced swim test, with the exception on post-stress condition. These effects on adaptation to stress induced by serotonin type 7 receptor activation were prevented by previous treatment with SB 258741.Conclusions: Our data support the idea that activation of median raphe nucleus serotonin 7 receptor is important to the development of adaptation to stress. [ABSTRACT FROM AUTHOR]

• Commd1 mRNA knockout occurred only in the maternally derived line. • Commd1 knockout affected stereotypy and depressive-like behavior but not locomotion. • The presence of Cre , not Commd1 knockout , resulted in differences in sensorimotor habituation. • Demonstrated in vivo behavioral role for Commd1 for the first time. In this study we focused on gene expression and behavioral differences in mice with brain-specific Commd1 knockout. Commd1 is an imprinted gene with preferential maternal expression, residing within a larger genomic region previously found to affect sensorimotor gating. In this study, individuals harboring a conditional Commd1 mutant allele were bred with Syn1- Cre animals, paying special attention to the parent of origin of the Commd1 mutation. Analysis of mRNA levels of Commd1 and phenotypic tests, including the open field, sensorimotor gating, and the forced swim test, were conducted on offspring with either maternally or paternally derived Commd1 knockout. We found that measurable Commd1 mRNA knockout occurred only in the maternally derived line and affected stereotypy and depressive-like behavior without differences in total locomotion compared to controls. Interestingly, we found that maternal knockout animals exhibited decreased time swimming and increased time immobile when compared to maternal and paternal wild type, and paternal knockout animals. However, there were no differences in climbing behavior between genotypes. This study demonstrates an in vivo behavioral role for Commd1 for the first time and demonstrates the need for careful interpretation of experimental results involving Cre-based knockout systems. [ABSTRACT FROM AUTHOR]

Symptoms of trauma and stressor related disorders such as post-traumatic stress disorder (PTSD) often develop well after the traumatic experience has occurred, and so identifying early predictors of risk or resilience is important for the implementation of interventional therapies. For example, passive coping strategies such as tonic immobility and peritraumatic dissociation during the trauma itself are risk factors for the developments of PTSD, especially in women. However, discrete, sex-specific coping responses that predict later outcomes in animal models have not been rigorously defined. Recently, we identified an active, escape-like response exhibited primarily by a subset of female rats in a classic auditory fear conditioning task (“darting”). Here, we asked whether darting during conditioning predicted active responding in a single forced swim (SFS) session to study the potential for darting to reflect a trait-like behavioral strategy that translated across stress models. Male and female Sprague-Dawley (SD) rats were tested in auditory fear conditioning acquisition and memory tests to identify Darters, and then a 15-min SFS 2 weeks later. We observed a significant effect of sex in conditioned freezing behavior, with males exhibiting greater freezing than females across conditioning and testing trials in comparison to females. However, females demonstrated higher velocities in response to shock presentations, and were more likely to exhibit darting behavior in response to the conditioned stimulus (CS). In SFS measures, females engaged in active behaviors such as climbing, head shaking, and diving in greater proportions than males, while males spent more time immobile throughout testing. Despite females exhibiting a more diverse behavioral repertoire in both tests, Darters did not differ from Non-darters in any SFS measure. These results suggest that the propensity to dart does not reflect a simple hyperactivity, and that despite conceptual overlap across the two tests (inescapable stress exposure and the ability to measure active vs. passive coping), the behavioral strategies engaged by an individual animal in each are likely driven by discrete mechanisms. We discuss potential challenges in interpretation of standard behavioral outcomes in classic models across the sexes, and consider the potential need for novel models that better tap into motivational states in females.

Corticotropin releasing factor (CRF) is a key component of stress responsivity, modulating related behaviors including anxiety and reward. Difficulties identifying CRF neurons, using traditional approaches including immunohistochemistry, has led to the development of a number of transgenic CRF reporter mice. The Crh-IRES-Cre: :Ai14 (tdTomato) reporter mouse is increasing in popularity as a useful tool to assess the localization, connectivity and function of CRF neurons in various stress-related behaviors. However, without proper characterization of reporter expression, the in vivo and in vitro manifestations resulting from the manipulation of these cells must be interpreted with caution. Here we mapped the distribution of tdTomato-expressing CRF cells throughout the rostro-caudal extent of the Crh-IRES-Cre: :Ai14 mouse brain. To determine if reporter expression faithfully reproduced native CRF expression, we assessed the colocalization of CRF expression with tdTomato reporter expression across several brain regions. Good concordance was observed in the extended amygdala and paraventricular nucleus of the hypothalamus (PVN), while discrepancies were observed within the lateral hypothalamus and hippocampus. Finally, we examined the activation of CRF neurons in Crh-IRES-Cre: :Ai14 mice in response to different types of stressors using Fos immunohistochemistry. Acute psychological (swim) and pharmacological (yohimbine) stress stimulated Fos-protein expression in PVN CRF neurons. Interestingly though, exposure to four daily restraint stress sessions followed by a novel acute stressor did not further recruit CRF neurons across any brain region examined. Our results highlight the importance of thoroughly characterizing reporter mice before use and suggest that acute versus repeated stress may differentially impact the CRF system. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'. • The Crh-IRES-Cre: :Ai14 mouse had faithful reporter expression in BNST and PVN. • The Crh-IRES-Cre: :Ai14 mouse had unfaithful reporter expression in PVT and LH. • Acute stress stimulated Fos expression in PVN CRF neurons. • Chronic stress followed by a novel acute stressor did not recruit CRF neurons. [ABSTRACT FROM AUTHOR]

Stress facilitates pain perception and sensitizes pain pathways, but the underlying mechanism is still unclear. The purpose of this study was to investigate whether the activation of 5-hydroxytryptamine (5-HT) subtype-3 receptor in the spinal cord contributes to somatic hyperalgesia induced by repeated three-day forced swim in the estradiol replacement rats after ovariectomy. Somatic sensitivity was assessed by thermal withdrawal latency to radiant heat and mechanical withdrawal threshold to von Frey filaments. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord was examined by Western blot. Repeated forced swim stress reduced the thermal withdrawal latency and mechanical withdrawal threshold, and the presence of estradiol exaggerated this hyperalgesia. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord increased significantly following repeated forced swim in estradiol replacement rats. Intrathecal injection of 5-HT3 receptor antagonist Y-25130 blocked the somatic hyperalgesia induced by forced swim stress. These data indicate that 5-HT3 receptor activation through the descending facilitation system contributes to the somatic hyperalgesia evoked by forced swim stress. The results may provide a new therapeutic avenue for alleviating pain induced by stress. [ABSTRACT FROM AUTHOR]

Depression-like behavior during lactation may relate to changes in the hypothalamic-pituitary-adrenal (HPA) axis, brain monoamines, and brain amino acid metabolism. This study investigated how the behavior, HPA axis activity, brain monoamines, and brain free amino acid metabolism of rats were changed by stress or lactation period. Rats were separated into four groups: (1) control lactating (n = 6), (2) stress lactating (n = 6), (3) control virgin (n = 7), and (4) stress virgin (n = 7) and restrained for 30 min a total of ten times (once every other day) from postnatal day (PND) 1. Depression-like behavior in the forced swimming test (FST) on PND 10 and concentration of corticosterone in plasma, as well as monoamines and L-amino acids including β-alanine, γ-aminobutyric acid, cystathionine, 3-methyl-histidine and taurine in the prefrontal cortex and hypothalamus on PND 19 were measured. The plasma corticosterone concentration, measured just after restraint stress, was significantly higher in the stress groups, versus the control groups, but there were no significant differences between control and stress lactating groups. Depression-like behavior (immobility) in the FST was significantly lower in the lactating groups, versus the virgin groups. Stress enhanced dopamine and glutamate, and decreased threonine and glycine concentrations in the hypothalamus. In addition, 3-methoxy-4-hydroxyphenylglycol (MHPG), threonine and ornithine concentrations in the prefrontal cortex were significantly higher in the lactating groups compared with the virgin groups. Changes in plasma corticosterone concentration, monoamine, and amino acid metabolism may relate to stress-induced depression-like behavior in lactating rats. This study revealed that reduced depression-like behavior in lactating, relative to virgin rats, was associated with changes in monoamine and amino acid metabolism in the prefrontal cortex of the brain. In addition, the effect of stress on monoamine and amino acid metabolism is prominently observed in the hypothalamus and may be related to neuroendocrine stress axis activity and secretion of corticosterone. This study suggested that stress-induced depression-like behavior may be associated with several changes in the stress axis, brain monoamines, and brain amino acid metabolism. These parameters were associated with attenuated depression-like behavior in lactating rats. [ABSTRACT FROM AUTHOR]

Introduction: Orexin-containing neurons exist in the lateral hypothalamic region, sending their projections toward mesolimbic regions such as the Ventral Tegmental Area (VTA). Methods: In the current study, a Reinstatement model is used to examine the effects of intra-VTA administration of SB334867 as an Orexin-1 Receptor (OX1R) antagonist on drug priming- and Forced Swim Stress (FSS)-induced reinstatement of morphine. Eighty-eight male adult albino Wistar rats, weighing 200-280 g, were bilaterally implanted by cannulas into the VTA. We induced the Conditioned Place Preference (CPP) by Subcutaneous (SC) injection of morphine (5 mg/kg) daily in three days. Then, the CPP score was calculated. After a 24-h “off” period following achievement of extinction criterion, the rats were tested for drug priming-induced reinstatement by a priming dose of morphine (1 mg/kg, SC) and for FSS-induced reinstatement 10 min after FSS. In the next experiments, the animals received different doses of intra-VTA administration of SB334867 (0.3, 3, and 1 nM/0.3 μL 12% DMSO per side) and bilaterally were subsequently tested for FSS- and morphine priming-induced reinstatement. Results: Our findings indicated that the FSS could induce the reinstatement of seeking behaviors. Furthermore, intra-VTA administration of OX1R antagonists suppressed FSS- and drug priming-induced reinstatement dose-dependently. Conclusion: It is concluded that FSS and drug priming-induced reinstatement might be mediated, at least in part, by stimulation of orexin receptors in the VTA. [ABSTRACT FROM AUTHOR]

Rationale: Pre-clinical and clinical studies have suggested that the antidepressant efficacy of escitalopram (ESC) can be augmented by co-administration of aripiprazole (ARI). Objective: To establish if the effects of ESC + ARI can be altered by modulating the 5-HT1a receptor. Methods: Sprague-Dawley male rats received ESC + ARI (10 and 2 mg/kg/day, respectively, via osmotic or by cumulative injections), as well as the 5-HT1a antagonist WAY-100635 (WAY; 0.01–1 mg/kg) and the 5-HT1a agonist 8-OH-DPAT (DPAT; 0.3–1 mg/kg) prior to testing in locomotion chambers and in the forced swim test (FST). Expression of the 5-HT1a receptor mRNA in the dorsal raphe nucleus, hippocampus, septum, and entorhinal cortex was also assessed. Results: WAY generally synergized, while DPAT antagonized, the effect of ESC + ARI on motor activity. All groups showed significantly lower 5-HT1a mRNA in the dorsal raphe nucleus. In the hippocampus, ESC + ARI and WAY + ESC + ARI groups displayed equivalent elevations of 5-HT1a mRNA, but this was not observed in groups that received DPAT + ESC + ARI. Finally, the addition of ARI to ESC augmented the effect that ESC alone had on reducing immobility in the FST. Importantly, WAY antagonized this effect, while DPAT had no consequences. Conclusions: Taken together, these results in rats indicate that the 5-HT1a receptor is involved in the behavioral and brain region-specific mRNA effects of ESC + ARI. [ABSTRACT FROM AUTHOR]

Abstract Adolescence represents a critical period of neurodevelopment, defined by structural and synaptic pruning within the prefrontal cortex. While characteristic of typical development, this structural instability may open a window of vulnerability to developing neuropsychiatric disorders, including depression. Thus, therapeutic interventions that support or expedite neural remodeling in adolescence may be advantageous. Here, we inhibited the neuronally-expressed cytoskeletal regulatory factor Rho-kinase (ROCK), focusing primarily on the clinically-viable ROCK inhibitor fasudil. ROCK inhibition had rapid antidepressant-like effects in adolescent mice, and its efficacy was comparable to ketamine and fluoxetine. It also modified levels of the antidepressant-related signaling factors, tropomyosin/tyrosine receptor kinase B and Akt, as well as the postsynaptic marker PSD-95, in the ventromedial prefrontal cortex (vmPFC). Meanwhile, adolescent-typical dendritic spine pruning on excitatory pyramidal neurons in the vmPFC was expedited. Further, vmPFC-specific shRNA-mediated reduction of ROCK2, the dominant ROCK isoform in the brain, had antidepressant-like consequences. We cautiously suggest that ROCK inhibitors may have therapeutic potential for adolescent-onset depression. Highlights • Adolescence is a critical period of neurodevelopment. • New antidepressants for adolescents are needed. • Therapeutic interventions that expedite neural remodeling may be advantageous. • Inhibiting the cytoskeletal regulatory factor Rho-kinase had antidepressant effects. • Inhibition hastened structural refinement in the prefrontal cortex and elevated PSD95. [ABSTRACT FROM AUTHOR]

Highlights • 5-fluorouracil induced fatigue and decreased food intake, body weight, and WBCs. • Fatigue was detectable using VWRA and TFT, but not OFT, FST, or exercise capacity. • Taltirelin alleviated fatigue in the TFT. • Methylphenidate alleviated fatigue in the TFT and increased locomotor activity. Abstract Fatigue is a common symptom in many diseases and disorders and can reduce quality of life, yet lacks an adequate pharmacological intervention. To identify and develop such interventions, and to better understand fatigue, additional preclinical research is necessary. However, despite numerous mouse behavioral assays reportedly detecting fatigue-like behavior, the assumption that fatigue-like behavior is detected in many assays has not been validated through a cross-assay study. Thus, we modeled fatigue in mice by administering 5-fluorouracil, a chemotherapy drug known to cause fatigue in humans and fatigue-like behavior in mice, then evaluated its effects via voluntary wheel running activity (VWRA), locomotor activity in the open field test (OFT), immobility in the forced swim test (FST), and distance run in the treadmill fatigue test (TFT) and treadmill exercise capacity test. Additionally, taltirelin or methylphenidate was administered to alleviate fatigue-like behavior. As a result of 5-fluorouracil treatment, VWRA and the TFT were markedly reduced, indicating fatigue. The OFT, FST, and treadmill exercise capacity test, however, failed to detect fatigue-like behavior. Interestingly, both taltirelin and methylphenidate alleviated fatigue-like behavior in TFT. These data suggest that, of the current assays, only the TFT and VWRA should be expected to detect fatigue-like behavior. Moreover, this study provides additional evidence that taltirelin may provide a novel treatment for chemotherapy-induced fatigue and warrants further evaluation as an anti-fatigue therapeutic. [ABSTRACT FROM AUTHOR]

Symptoms of trauma and stressor related disorders such as post-traumatic stress disorder (PTSD) often develop well after the traumatic experience has occurred, and so identifying early predictors of risk or resilience is important for the implementation of interventional therapies. For example, passive coping strategies such as tonic immobility and peritraumatic dissociation during the trauma itself are risk factors for the developments of PTSD, especially in women. However, discrete, sex-specific coping responses that predict later outcomes in animal models have not been rigorously defined. Recently, we identified an active, escape-like response exhibited primarily by a subset of female rats in a classic auditory fear conditioning task ("darting"). Here, we asked whether darting during conditioning predicted active responding in a single forced swim (SFS) session to study the potential for darting to reflect a trait-like behavioral strategy that translated across stress models. Male and female Sprague-Dawley (SD) rats were tested in auditory fear conditioning acquisition and memory tests to identify Darters, and then a 15-min SFS 2 weeks later. We observed a significant effect of sex in conditioned freezing behavior, with males exhibiting greater freezing than females across conditioning and testing trials in comparison to females. However, females demonstrated higher velocities in response to shock presentations, and were more likely to exhibit darting behavior in response to the conditioned stimulus (CS). In SFS measures, females engaged in active behaviors such as climbing, head shaking, and diving in greater proportions than males, while males spent more time immobile throughout testing. Despite females exhibiting a more diverse behavioral repertoire in both tests, Darters did not differ from Non-darters in any SFS measure. These results suggest that the propensity to dart does not reflect a simple hyperactivity, and that despite conceptual overlap across the two tests (inescapable stress exposure and the ability to measure active vs. passive coping), the behavioral strategies engaged by an individual animal in each are likely driven by discrete mechanisms. We discuss potential challenges in interpretation of standard behavioral outcomes in classic models across the sexes, and consider the potential need for novel models that better tap into motivational states in females. [ABSTRACT FROM AUTHOR]

Kaiso is a methyl DNA-binding protein, which participates in the epigenetic regulation of gene expression. It binds methylated DNA with its zinc-finger domain and recruits repressive protein complexes to the methylated DNA fragments by the interaction of the BTB/POZ domain with the complex of NCoR corepressor and histone deacetylase, thereby performing transcription repression. A Kaiso-deficient mouse strain (KO) with the C57BL/6 strain background has been bred. Here we compare the behavior of KO mice and wild-type control C57BL/6 mice (WT) in the classic battery of behavioral tests, including the open field, elevated plus maze, and forced swim tests. We have shown that knockout of the Kaiso gene increases the locomotory and exploratory activities of KO mice in the open field test. Kaiso-deficient mice spend more time in the center of the open field than WT mice. No effect of Kaiso gene knockout on anxietyrelated behavior has been observed in the elevated plus-maze. However, Kaiso gene deficiency produces a pronounced antidepressant-like effect in the forced swim test: Unlike WT mice, KO mice do not show any depressive-like freezing in this test. These results are the first piece of experimental evidence for the involvement of Kaiso protein in the regulation of brain functioning and beha­vior. The Kaiso-deficient strain is a new and promising model of the genetic, molecular, and neuronal mechanisms mediating the epigenetic regulation of brain functions and behavior.

While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic “biomarkers” could be extracted to classify different types of behavioral experience. To begin to address this question, male and female mice were subjected to either a Fixed Interval (FI) schedule of food reward, or a single episode of forced swim followed by restraint stress, or no explicit behavioral experience after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) and frontal cortex (FC). The specific nature of the behavioral experience differentiated profiles of PTHMs in a sex- and brain region-dependent manner, with all 4 PTHMs changing in parallel in response to different behavioral experiences. These different behavioral experiences also modified the pattern of correlations of PTHMs both within and across FC and HIPP. Unexpectedly, highly robust correlations were found between global PTHM levels and behavioral performances, suggesting that global PTHMs may provide a higher-order pattern recognition function. Further efforts are needed to determine the generality of such findings and what characteristics of behavioral experience are critical for modulating PTHM responses.

While it is clear that behavioral experience modulates epigenetic profiles, it is less evident how the nature of that experience influences outcomes and whether epigenetic/genetic "biomarkers" could be extracted to classify different types of behavioral experience. To begin to address this question, male and female mice were subjected to either a Fixed Interval (FI) schedule of food reward, or a single episode of forced swim followed by restraint stress, or no explicit behavioral experience after which global expression levels of two activating (H3K9ac and H3K4me3) and two repressive (H3K9me2 and H3k27me3) post-translational histone modifications (PTHMs), were measured in hippocampus (HIPP) and frontal cortex (FC). The specific nature of the behavioral experience differentiated profiles of PTHMs in a sex- and brain region-dependent manner, with all 4 PTHMs changing in parallel in response to different behavioral experiences. These different behavioral experiences also modified the pattern of correlations of PTHMs both within and across FC and HIPP. Unexpectedly, highly robust correlations were found between global PTHM levels and behavioral performances, suggesting that global PTHMs may provide a higher-order pattern recognition function. Further efforts are needed to determine the generality of such findings and what characteristics of behavioral experience are critical for modulating PTHM responses. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to determine whether hyperbaric oxygen (HBO) therapy causes attenuation of traumatic brain injury (TBI)–induced depression-like behavior and its associated anti-neuroinflammatory effects after fluid percussion injury. Methods Anesthetized male Sprague-Dawley rats were divided into 3 groups: sham operation plus normobaric air (NBA) (21% oxygen at 1 absolute atmosphere [ATA]), TBI plus NBA, and TBI plus HBO (100% oxygen at 2.0 ATA). HBO was applied immediately for 60 min/d after TBI for 3 days. Depression-like behavior was tested by a forced swimming test, motor function was tested by an inclined plane test, and infarction volume was tested by triphenyltetrazolium chloride (TTC) staining on days 4, 8, and 15. Neuronal apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling assay), microglial (marker OX42) activation, and tumor necrosis factor (TNF)–α expression in microglia in the hippocampus CA3 were measured by immunofluorescence methods. Results Compared with the TBI controls, without significant changes in TTC staining or in the motor function test, TBI-induced depression-like behavior was significantly attenuated by HBO therapy by day 15 after TBI. Simultaneously, TBI-induced neuronal apoptosis, microglial (marker OX42) activation, and TNF–α expression in the microglia in the hippocampus CA3 were significantly reduced by HBO. Conclusions Our results suggest that HBO treatment may ameliorate TBI-induced depression-like behavior in rats by attenuating neuroinflammation, representing one possible mechanism by which depression-like behavior recovery might occur. We also recommend HBO as a potential treatment for TBI-induced depression-like behavior if early intervention is possible. [ABSTRACT FROM AUTHOR]

Background: The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory.Methods: Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-α expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI.Results: TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days.Conclusions: Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-α expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior. [ABSTRACT FROM AUTHOR]

Early-life stress is thought to increase later vulnerability for developing depressive illness by sensitizing underlying stress-responsive systems. Guinea pig pups separated from their mother and isolated in a novel cage for 3 hr exhibit a sensitized depressive-like behavioral response when separated again the following day as well as weeks later. The behavioral response and its sensitization appear to be mediated by inflammatory factors. To determine if this sensitization is specific to the separation response or if it reflects a broader underlying depressive-like state, guinea pig pups that had either been separated for 3 hr or remained with their mothers were observed in the forced swim test the following 3 days. Earlier separation was found to increase the duration of immobility, a measure sensitive to antidepressant treatment. These results support the use of the guinea pig as a model for examining mechanisms of inflammatory-mediated sensitization of depression following stress in early life. [ABSTRACT FROM AUTHOR]

In the wild, animals are exposed to an ever-changing array of sensory stimuli. The captive environment, by contrast, is generally much more impoverished in terms of the cues it offers the animals housed within. In a bid to remedy this, and promote better welfare, mice (Mus musculus) were exposed to two conditions: no auditory stimulation, and stimulation with classical music. In all experiments, a battery of behavior tests was used. The results demonstrated significantly decreased immobility in the forced swim, increased enclosed arm entries in the plus-maze, and decreased immobility in the open-field, in animals that had been pre-exposed to music 24h earlier, suggesting that changes in mouse motor activity were caused by classical music. This study led to the conclusion that environmental enrichment may have profound effects on the behavior of mice in behavioral tests, and that classical music can be a relatively simple method of contributing to the well-being of captive mice, but it can affect the results of experiments such as forced swimming.

Vasopressin, a nonapeptide, signaling both as hormone in the blood and neuromodulator/neurotransmitter in the brain is considered to be causally involved in the pathological changes underlying anxiety and depression. In the present review we summarize experimental data obtained with Brattleboro rats as a model of congenital vasopressin-deficiency to test the hypothesis that central vasopressin signaling contributes to anxiety- and depression-like behavior. Male, female and lactating rats were studied. We focused on the paraventricular nucleus of the hypothalamus (PVN) and the septum, two brain areas in which vasopressin is proposed to control the endocrine and behavioral stress response, respectively. The presented data support the hypothesis that the behavioral changes seen in these rats are brought about by an altered vasopressin signaling at the brain level. Whereas vasopressin synthesized and released within the hypothalamus is primarily involved in endocrine regulation, vasopressin signaling in other brain areas may contribute to anxiety- and depression-like behavioral parameters. Further studies in this context might focus particularly on the interplay between extra-hypothalamic brain areas such as the septum and the medial amygdala. [ABSTRACT FROM PUBLISHER]

Kaiso is a methyl-DNA-binding protein, which is involved in the epigenetic regulation of gene expression. It binds methylated DNA with its zinc-finger domain and recruits repressive protein complexes to the methylated DNA fragments due to the interaction of the BTB/POZ domain with the complex of the NCoR corepressor and histone deacetylase, thereby repressing transcription. A Kaiso-deficient mouse strain (KO) with the C57BL/6 strain background has been developed. Here we compared the behavioral features of KO mice and wild-type (WT) control C57BL/6 mice in the classic battery of behavioral tests, including an open field, elevated plus-maze, and forced swim tests. We have shown that the Kaiso knockout gene increased the locomotor and exploratory activities of KO mice in the open field test. The Kaiso-deficient mice spent more time in the center of the open field than WT mice. No effect of the Kaiso knockout gene on anxietyrelated behavior has been observed in the elevated plus-maze. However, the Kaiso gene deficiency produced a pronounced antidepressant-like effect in the forced swim test. In contrast to WT mice, KO mice did not show any depressive-like freezing in this test. These results are the first experimental evidence of the involvement of Kaiso protein in the regulation of brain functions and behavior. The Kaiso KO mice are a new and promising model for studying genetic, molecular, and neuronal mechanisms, mediating the epigenetic regulation of brain functions and behavior. [ABSTRACT FROM AUTHOR]

Abscisic acid (ABA), a crucial phytohormone, is distributed in the brains of mammals and has been shown to have antidepressant effects in the chronic unpredictable mild stress test. The forced swim test (FST) is another animal model that can be used to assess antidepressant-like behavior in rodents. Here, we report that the antidepressant effects of ABA are associated with sensitivities to the FST in mice. Based on mean immobility in the 5-min forced swim pre-test, ICR mice were divided into short immobility mice (SIM) and long immobility mice (LIM) substrains. FST was carried out 8 days after drug administration. Learned helplessness, as shown by increased immobility, was only observed in SIM substrain and could be prevented by an 8-day ABA treatment. Our results show that ABA has antidepressant effects in SIM substrain and suggest that mice with learned helplessness might be more suitable for screening potential antidepressant drugs. [ABSTRACT FROM AUTHOR]

There have been numerous studies into the interaction between stress and addictive drugs, yet few have specifically addressed how the organism responds to stress when under the influence of psychostimulants. Thus, we studied the effects of different acute stressors (immobilization, interleukin-1β and forced swimming) in young adult male rats simultaneously exposed to amphetamine (AMPH, 4 mg/kg SC), evaluating classic biological markers. AMPH administration itself augmented the plasma hypothalamic-pituitary-adrenal (HPA) hormones, adrenocorticotropin (ACTH) and corticosterone, without affecting plasma glucose levels. By contrast, this drug dampened the peripheral HPA axis, as well as the response of glucose to the three stressors. We also found that AMPH administration completely blocked the forced swim-induced expression of the corticotropin-releasing hormone (hnCRH) and it partially reduced c-fos expression in the paraventricular nucleus of the hypothalamus (PVN). Indeed, this negative synergy in the forced swim test could even be observed with a lower dose of AMPH (1 mg/kg, SC), a dose that is usually received in self-administration experiments. In conclusion, when rats that receive AMPH are subjected to stress, a negative synergy occurs that dampens the prototypic peripheral physiological response to stress and activation of the PVN. [ABSTRACT FROM AUTHOR]

Background: Withania somnifera (WS), Indian ginseng/ashwagandha, is a common household plant. Its commercially available aqueous or ethanolic root powder extract containing the active substance withanolides is known to enhance physical endurance (stamina). The potency of crude root powders, especially post-extraction, is unknown. Objectives: The aim of this study was to compare the efficacy of crude root powder of WS post-extraction with commercial root preparation in enhancing the physical endurance of mice using forced swim endurance model. Materials and Methods: Male Swiss albino mice, 6–8 weeks old with mean (standard deviation) weight of 35.17 (3.36) g, were randomized into three groups of six animals each: control – carboxymethyl cellulose 0.5%, standard – commercial root preparation of WS (100 mg/kg), and test – crude root powder post-extraction (100 mg/kg). Drugs were administered per oral, once daily, for 7 days. On the 8th day, animals were allowed to swim till exhaustion in a propylene tub of dimension 25 cm radius and 30 cm height, with water level at 15 cm. The end point of swim endurance was when the mice near drowned. Results: There was no significant difference in body weight of mice between groups. One-way ANOVA between groups for drowning time was significant (F[2,15] = 12.771, P = 0.001). Tukey's post hoc test was significant for test versus control (P < 0.001) and standard versus control (P = 0.047). However, test versus standard was not statistically significant (P = 0.069). Conclusion: Hence, we conclude that crude root powder of WS after extraction also possesses physical endurance enhancing property and may be used to enhance the stamina. Abbreviations Used: ANOVA: Analyis of Variance; CI: Confidence Interval; CMC: Carboxy Methyl Cellulose; HPLC: High Performance Liquid Chromatography; MeSH: Medical Subject Heading; SD: Standard Deviation; TLC: Thin Layer Chromatography; WS: Withania somnifera [ABSTRACT FROM AUTHOR]

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10–20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6–5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia. • Short term stress does not induce modifications in nociception. • Short term stress reduces morphine effect in orofacial but not in limb pain models. • The reduced antinociceptive effect of morphine is mediated by opioid receptors. • Constipation induced by morphine is not affected by short-term stress. • Prevention of stress even of short duration, may improve opioid antinociception. [ABSTRACT FROM AUTHOR]

Objective: The link between alterations in circadian rhythms and depression are well established, but the underlying mechanisms are far less elucidated. We investigated the circadian characteristics of immobility behavior in wild type (WT) mice and mice with mutations in core Clock genes. Methods: All mice were tested with forced swim test (FST) at 4 h intervals. Results: These experiments revealed significant diurnal rhythms associated with immobility behavior in both male and female WT mice with sex-different circadian properties. In addition, male mice showed significantly less immobility during the night phase in comparison to female mice. Female Per1Brdm1 mice also showed significant rhythmicity. However, the timing of rhythmicity was very different from that observed in female wild type mice. Male Per1Brdm1 mice showed a pattern of rhythmicity similar to that of wild type mice. Furthermore, female Per1Brdm1 mice showed higher duration of immobility in comparison to male Per1Brdm1 mice in both daytime and early night phases. Neither Per2Brdm1 nor ClockÎ"19 mice showed significant rhythmicity, but both female Per2Brdm1 and ClockÎ"19 mice had lower levels of immobility, compared to males. Conclusions: This study highlights the differences in the circadian characteristics of immobility induced by FST in WT, ClockÎ"19, Per1, and Per2 deficient mice. [ABSTRACT FROM AUTHOR]

Rationale: Glucocorticoids facilitate coping with stress, but their high levels have been also implicated in mood disorders. Due to this duality, the role of glucocorticoid signaling in the development of the first episodes of stress-induced depression remains unclear. Objectives: To address this issue, effects of the glucocorticoid signal modulation on depressive-like behavior during pretest and test Porsolt swim sessions were examined. Methods: Metyrapone (MET; 150 mg/kg, i.p.) was injected 3 h before pretest to block stress-induced increase in corticosterone levels. Dexamethasone (DEX; 0.2 mg/kg, s.c.) was applied to MET-treated rats 1 h before both pretest and test sessions. In addition to behavior during these sessions, glucocorticoid receptor (GR) expression was analyzed by immunohistochemistry 2 h after the second swim. Results: In pretest, MET-treated rats exhibited increased latency to immobility and shortened immobility. DEX reversed the behavioral effects of MET in the pretest. In the test, animals from MET + DEX group unexpectedly exhibited an antidepressant-like behavior. Swim stress increased GR expression in the frontal cortex irrespective of the pharmacological treatment. A significant elevation in GR expression was found in the prefrontal cortex (PFC) of stressed MET + DEX-treated rats and in the PFC of unstressed rats 6 h after injection of DEX alone. Conclusion: The data suggest that the increase in glucocorticoid levels under swim stress during pretest directly contributes to the development of the immobility response. Transition of DEX effect from prodepressant in the pretest to an antidepressant in the test was associated with the elevation in the PFC GR expression. [ABSTRACT FROM AUTHOR]

Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic–pituitary–adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent. PFC GR knock-down increased behavioral sensitivity to imipramine, with imipramine-treated PFC-GRKD but not PFC-GFP mice exhibiting significant decreases in depression-like immobility during forced swim. PFC GR deletion did not alter general locomotor activity. The 30 mg/kg dose of imipramine increased plasma corticosterone levels immediately after a 5-min forced swim, but PFC GR knock-down had no significant effect on plasma corticosterone under these experimental conditions. We conclude that PFC GR knock-down, likely limited to the medial prelimbic and anterior cingulate cortices, can increase behavioral sensitivity to antidepressants. These findings indicate a novel role for PFC GR in influencing antidepressant response. [ABSTRACT FROM AUTHOR]

Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt's forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. [ABSTRACT FROM AUTHOR]