Depression-like State Research Articles

Blockade of the Sigma-1 Receptor Relieves Cognitive and Emotional Impairments Associated to Chronic Osteoarthritis Pain.

Osteoarthritis is the most common musculoskeletal disease worldwide, often characterized by degradation of the articular cartilage, chronic joint pain and disability. Cognitive dysfunction, anxiety and depression are common comorbidities that impact the quality of life of these patients. In this study, we evaluated the involvement of sigma-1 receptor (σ1R) on the nociceptive, cognitive and emotional alterations associated with chronic osteoarthritis pain. Monosodium iodoacetate (MIA) was injected into the knee of Swiss-albino CD1 mice to induce osteoarthritis pain, which then received a repeated treatment with the σ1R antagonist E-52862 or its vehicle. Nociceptive responses and motor performance were assessed with the von Frey and the Catwalk gait tests. Cognitive alterations were evaluated using the novel object recognition task, anxiety-like behavior with the elevated plus maze and the zero-maze tests, whereas depressive-like responses were determined using the forced swimming test. We also studied the local effect of the σ1R antagonist on cartilage degradation, and its central effects on microglial reactivity in the medial prefrontal cortex. MIA induced mechanical allodynia and gait abnormalities that were prevented by the chronic treatment with the σ1R antagonist. E-52862 also reduced the memory impairment and the depressive-like behavior associated to osteoarthritis pain. Interestingly, the effect of E-52862 on depressive-like behavior was not accompanied by a modification of anxiety-like behavior. The pain-relieving effects of the σ1R antagonist were not due to a local effect on the articular cartilage, since E-52862 treatment did not modify the histological alterations of the knee joints. However, E-52862 induced central effects revealed by a reduction of the cortical microgliosis observed in mice with osteoarthritis pain. These findings show that σ1R antagonism inhibits mechanical hypersensitivity, cognitive deficits and depressive-like states associated with osteoarthritis pain in mice. These effects are associated with central modulation of glial activity but are unrelated to changes in cartilage degradation. Therefore, targeting the σ1R with E-52862 represents a promising pharmacological approach with effects on multiple aspects of chronic osteoarthritis pain that may go beyond the strict inhibition of nociception.

Cytokine Content in the Hypothalamus and Hippocampus of C57Bl/6J Mice with Depressive-Like Behavior.

The content of pro- and anti-inflammatory cytokines in the hypothalamus, hippocampus, and blood serum of C57Bl/6J mice with depressive-like behavior induced by 20-day social stress was analyzed in 4 h after immune stimulation with LPS (250 μg/kg). These animals are characterized by a tendency to an increase in the blood content of IL-6 and a decrease in the level of IL-10. Changes in cytokine content in the brain of mice with depressive-like state developed under these conditions were observed only in the hippocampus: the levels of IL-1β, IL-6, TNFα, and IL-10 increased and the content of IFNγ decreased in comparison the corresponding parameters in the controls (not exposed to social stress) and aggressive animals. No changes in the levels of IL-2, IL-4, and IL-17 were revealed in the hypothalamus and hippocampus.

Chronic Exposure to Ultrasonic Frequencies Selectively Increases Aggression in Rats

We studied aggression in male Sprague-Dawley rats in a model of a depressive-like state induced by unpredictable treatment with ultrasonic waves with the frequencies of 20-45 kHz for 1, 2 or 3 weeks. We did not find any increase in the number of animals exhibiting aggression in the "resident-intruder" test after the treatment of any selected duration. However, the aggressive animals exposed to ultrasound exhibited the substantially increased number of attacks and their total duration as well as decreased latency of the first attack compared to the respective indices in the animals of the control group. Taking this into account, it is possible to suggest that the initial level of aggression increases in a model of ultrasonic chronic stress.

Sex-Specific Effects of Stress on Mood-Related Gene Expression

Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and “four core genotypes” (FCG) mice to probe for sex-specific mechanisms. As predicted, based on previous implications in mood, stress impacted the expression of several dopamine-, GABA-, and glutamate-related genes. Some of these effects, specifically in the prefrontal cortex, were genetic sex-specific, with effects in XX mice but not in XY mice. Stress also impacted gene expression differently across the mesocorticolimbic circuit, with increased expression of mood-related genes in the prefrontal cortex and nucleus accumbens, but decreased expression in basolateral amygdala. Our results suggest that females are sensitive to the effects of chronic stress, partly due to their genetic sex, independent of gonadal hormones. Furthermore, these results point to the prefrontal cortex as the node in the mesocorticolimbic circuitry with the strongest female-specific effects.

Aberrant Expression of Collagen Gene Family in the Brain Regions of Male Mice with Behavioral Psychopathologies Induced by Chronic Agonistic Interactions.

Chronic agonistic interactions promote the development of experimental psychopathologies in animals: a depression-like state in chronically defeated mice and the pathology of aggressive behavior in the mice with repeated wins. The abundant research data indicate that such psychopathological states are associated with significant molecular and cellular changes in the brain. This paper aims to study the influence of a 20-day period of agonistic interactions on the expression patterns of collagen family genes encoding the proteins which are basic components of extracellular matrix (ECM) in different brain regions of mice using the RNA-Seq database. Most of differentially expressed collagen genes were shown to be upregulated in the hypothalamus and striatum of chronically aggressive and defeated mice and in the hippocampus of defeated mice, whereas downregulation of collagen genes was demonstrated in the ventral tegmental areas in both experimental groups. Aberrant expression of collagen genes induced by chronic agonistic interactions may be indicative of specific ECM defects in the brain regions of mice with alternative social experience. This is the first study demonstrating remodeling of ECM under the development of experimental disorders.

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice.

The kappa (κ) opioid receptor/dynorphin system modulates depression-like states and anhedonia, as well adaptations to stress and exposure to drugs of abuse. Several relatively short-acting small molecule κ-receptor antagonists have been synthesized, and their behavioral profile has been examined under some conditions. The hypothesis of this study is that pharmacological manipulations of the κ-receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice (n = 6-8) were examined for self-grooming behavior in the splash test (in which robust self-grooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The κ-agonist salvinorin A (0.56-1.8 mg/kg) produced dose-dependent decreases in self-grooming, a marker of anhedonia. The selectivity, potency, and duration of action of two relatively short-acting κ-antagonists, LY2444296 [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl) pyrrolidin-1-yl)methyl)phenoxy)benzamide] and LY2795050 [3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide], were studied for their effectiveness in preventing grooming deficits caused by salvinorin A (1.8 mg/kg). κ-selective doses of both LY2444296 (0.032-1 mg/kg) and LY2795050 (0.032-0.32 mg/kg) dose- and time-dependently prevented the grooming deficits caused by salvinorin A (1.8 m/kg). We also found that a κ-selective dose of each of these antagonists decreased immobility in the forced swim test, a common test of anti-anhedonia effects. This study shows that the κ-receptor system is involved in an ethologically relevant measure of anhedonia, and that κ-selective doses of these antagonists can produce effects consistent with rapid anti-anhedonia. SIGNIFICANCE STATEMENT: Activation of the κ-opioid receptor system results in grooming deficits in mice, an ethologically relevant marker of anhedonia. Shorter acting κ-antagonists are able to cause effects consistent with rapid antianhedonia.

Repeated bifenthrin exposure alters hippocampal Nurr-1/AChE and induces depression-like behavior in adult rats

Exposure to insecticides has been associated with depression-like symptoms, especially among occupationally exposed populations, such as farmers. Although the neurotoxicity of pyrethroids such as bifenthrin (BF) is well established, it is still unclear whether exposure to BF may have deleterious effects on the hippocampus and thus behavior. We verified the hypothesis that repeated exposure to BF in a rat model elicits neurochemical and behavioral alterations, the latter of which reflects depression-related symptoms. Adult male Wistar rats (n = 12 per group) were orally administered with different doses of BF (0.6 or 2.1 mg/kg body weight (b.w.)) on a daily basis for 60 days; control rats received the vehicle (corn oil). Different biochemical changes were assessed in the hippocampus, a region of the brain regulating spatial memory; behavioral tests were also conducted. Our results revealed depressive-like behaviors that were expressed by increased despair behavior in the Forced-swimming test. Repeated exposure to BF also decreased acetylcholinesterase (AChE) activity in the hippocampus and butyrylcholinesterase (BuChE) activity in plasma. A significant reduction in the activities of hippocampal membrane-bound ATPases (Na+/K+-ATPase and Mg2+-ATPase) was also observed in BF-treated rats compared to controls. Furthermore, a significant decrease in mRNA expression and protein synthesis of both AChE and orphan nuclear receptor (Nurr-1), as well as in the expression of muscarinic–cholinergic receptor (M1 mAchR) and nicotinic–cholinergic receptor (nAchR2α) was observed in the hippocampus of treated rats compared to controls. Also, BF exposure induced apoptosis as assessed by hippocampal Casp-3 protein levels. Our findings suggest that repeated exposure to BF affects hippocampal signaling and Nurr-1/AChE, and this was accompanied by depression-like state in adult rats.

The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling.

Brain insulin signaling is accounted for the development of a variety of neuropsychiatric disorders, such as anxiety and depression, whereas both inflammation and the activated renin-angiotensin system (RAS) are two major contributors to insulin resistance. Intriguingly, inflammation and RAS can activate each other, forming a positive feedback loop that would result in exacerbated unwanted tissue damage. To further examine the interrelationship among insulin signaling, neuroinflammation and RAS in the brain, the effect of repeated lipopolysaccharide (LPS) exposure and co-treatment with the angiotensin II (Ang II) receptor type 1 (AT1) blocker, candesartan (Cand), on anxiety and depression-like behaviors, RAS, neuroinflammation and insulin signaling was explored. Our results demonstrated that prolonged LPS challenge successfully induced the rats into anxiety and depression-like state, accompanied with significant neural apoptosis and neuroinflammation. LPS also activated RAS as evidenced by the enhanced angiotensin converting enzyme (ACE) expression, Ang II generation and AT1 expression. However, blocking the activated RAS with Cand co-treatment conferred neurobehavioral protective properties. The AT1 blocker markedly ameliorated the microglial activation, the enhanced gene expression of the proinflammatory cytokines and the overactivated NF-κB signaling. In addition, Cand also mitigated the LPS-induced disturbance of insulin signaling with the normalized phosphorylation of serine 307 and tyrosine 896 of insulin receptor substrate-1 (IRS-1). Collectively, the present study, for the first time, provided the direct evidence indicating that the inflammatory condition may interact with RAS to impede brain insulin pathway, resulting in neurobehavioral damage, and inhibiting RAS seems to be a promising strategy to block the cross-talk and cut off the vicious cycle between RAS and immune system.

Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine

Neuroinflammation is associated with increased vulnerability to diverse psychiatric conditions, including treatment-resistant major depressive disorder (MDD). Here we assessed whether high fat diet (HFD) induced neuroinflammation may be suitable to model a treatment-resistant depressive-like brain state in mice. Male and female mice were fed a HFD for 18 weeks, followed by quantitation of glucose tolerance, inflammatory markers of brain tissue (TNFα, IL-6, IL-1β, Iba-1), neural excitability in the prelimbic cortex (PLC), as well as assessment of emotional reactivity and hedonic behavior in a battery of behavioral tests. In addition, we assessed the behavioral responsiveness of mice to fluoxetine, desipramine, ketamine, and the Kv7 channel opener and anticonvulsant retigabine. HFD exposure led to glucose intolerance and neuroinflammation in male mice, with similar but non-significant trends in females. Neuroinflammation of males was associated with anxious-depressive-like behavior and defects in working memory, along with neural hyperexcitability and increased Ih currents of pyramidal cells in the PLC. The behavioral changes were largely resistant to chronic treatment with fluoxetine and desipramine, as well as ketamine. By contrast, retigabine (also known as ezogabine) normalized neural excitability and Ih currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.

Depression-like state behavioural outputs may confer beneficial outcomes in risky environments

Recent theories in evolutionary medicine have suggested that behavioural outputs associated with depression-like states (DLS) could be an adaptation to unpredictable and precarious situations. In animal models, DLS are often linked to diverse and unpredictable stressors or adverse experiences. Theoretically, there are a range of potential fitness benefits associated with behavioural inhibition (typical to DLS), as opposed to more active/aggressive responses to adverse or uncontrollable events. This stance of evolutionary medicine has to our knowledge not been tested empirically. Here we address a possible key benefit of behavioural inhibition in a comparative model for social stress (territorial rainbow trout). By treating fish with the fast-acting antidepressant ketamine, we reversed the behavioural inhibition (i.e. stimulated an increase in activity level) in subordinate fish. During confrontation with a previously unfamiliar larger, aggressive and dominant individual, this increase in activity led to higher amounts of received aggression compared to sham-treated subordinates. This suggests that the behavioural inhibition characterizing animal models of DLS is indeed an effective coping strategy that reduces the risk of injuries in vulnerable social situations.

Short-term withdrawal from repeated exposure to cocaine during adolescence modulates dynorphin mRNA levels and BDNF signaling in the rat nucleus accumbens

BackgroundEarly-life stressful events affect the neurobiological maturation of cerebral circuitries including the endogenous opioid system and the effects elicited by adolescent cocaine exposure on this system have been poorly investigated. Here, we evaluated whether cocaine exposure during adolescence causes short- or long-term alterations in mRNAs codifying for selected elements belonging to the opioid system. Moreover, since brain-derived neurotrophic factor (BDNF) may undergo simultaneous alterations with the opioid peptide dynorphin, we also evaluated its signaling pathway as well. MethodsAdolescent male rats were exposed to cocaine (20 mg/kg/day) from post-natal day (PND) 28 to PND42, approximately corresponding to human adolescence. After short- (PND45) or long-term (PND90) abstinence, prodynorphin-κ-opioid receptor (pDYN-KOP) and pronociceptin-nociceptin receptor (pN/OFQ-NOP) gene expression were evaluated in the nucleus accumbens (NAc) and hippocampus (Hip) together with the analysis of BDNF signaling pathways. ResultsIn the NAc of PND45 rats, pDYN mRNA levels were up-regulated, an effect paralled by increased BDNF signaling. Differently from NAc, pDYN mRNA levels were down-regulated in the Hip of PND45 rats without significant changes of BDNF pathway. At variance from PND45 rats, we did not find any significant alteration of the investigated parameters either in NAc and Hip of PND90 rats. ConclusionsOur results indicate that the short-term withdrawal from adolescent cocaine exposure is characterized by a parallel pDYN mRNA and BDNF signaling increase in the NAc. Given the depressive-like state experienced during short abstinence in humans, we hypothesize that such changes may contribute to promote the risk of cocaine abuse escalation and relapse.

Is boredom an animal welfare concern?

AbstractBoredom, while often casually attributed to non-human animals by both laypeople and scientists, has received little empirical study in this context. It is sometimes dismissed by others as anthropomorphic or a trivial concern in comparison to other welfare problems faced in captivity. Recent work on human boredom, however, has led to evidence that, far from being trivial, it can have serious consequences in the form of risky behaviour and reduced physical as well as mental health, and potentially contributes to social problems. Research on mink, supported by older literature on farm and laboratory animals, suggests that monotonous, stimulus-poor environments can induce an increased motivation for diverse stimuli, consistent with the experience of boredom. This experience is likely to be aversive and may lead to problems such as depression-like states or self-injurious behaviour if not addressed. Boredom should therefore be treated as an important welfare concern. Research is needed to find practical ways of identifying this state and to determine how widespread it is across species and which animals are most at risk. Possible ways of alleviating or avoiding this problem include offering animals in our care a choice in the level of stimulation they experience and opportunities to experience appropriate cognitive challenge.

Establishment and evaluation of a novel mouse model of peri/postmenopausal depression

Women are believed to be more vulnerable to develop depressive symptoms during the perimenopause compared to postmenopause. The traditional bilateral ovariectomy and chronic mild stress (CMS) stimulation animal model produces a postmenopausal depressive-like state but the transition from perimenopausal period to postmenopausal period was ignored. Thus we establish a novel animal model in which the mice were stimulated by CMS for three months and removed the ovaries by two-step operation, and then evaluate whether this novel model could be much better for preclinical study used as a peri/postmenopause depressive model. The present study systemically evaluated the changes induced by two-step ovariectomy plus CMS in the mice. The depression-like behaviors, the levels of corticosterone, estrogen, pro-inflammatory factors, neurotransmitters, as well as brain-derived neurotrophic factor were determined; the changes of estrogen receptors, serotonin receptors, uterine weight and bone microarchitecture were also observed. The results show that the behaviors and biochemical indexes of mice changed gradually over time. Our study suggests that this two-step ovariectomy operation plus CMS successfully establishes a more reasonable peri/postmenopausal depression animal model which effectively simulates the clinical symptoms of peri/postmenopausal depressive women.

Impaired fear memory extinction during adolescence is accompanied by the depressive-like behaviors

Fear is the emotion that is best understood in terms of brain mechanisms. And the management of fear memories is important when facing mental health disorders such as post-traumatic stress. Adolescence is a transitional stage of physical and psychological human development and the ability to deal with the fear memory in adolescence may be a potent factor for developing mental disorders in adulthood. However, little is known about the direct relationship between the ability to deal with the fear memory and appearance of depressive-like behaviors. To assess this, we used a model of associative learning to induce the fear memories and evaluated the depressive-related behaviors in the fear memory extinction process and its underlying cellular mechanisms from adolescent and adult mice. We found that, compared with adult mice, the adolescent mice exhibited impaired fear memory extinction in contextual fear conditioning extinction process. Meanwhile, impaired fear memory extinction was accompanied by more immobility time in forced swimming test, which was used to assess the depressive-like state. Consistent with this, we observed that long-term potentiation (LTP) induction in the hippocampal CA1 region of adolescent mice persistently larger in extinction process in adolescent mice, which was involved the presynaptic mechanism. Together, our results suggest that adolescent mice exhibited a disability to extinct the fear memory, and that this may lead to the depressive-like behaviors via presynaptic-mediated synaptic plasticity. These findings may give us a new insight in the knowledge of some mental disorders caused by persistent unpleasant memories.

Alteration of oxidative stress markers and behavior of rats in a novel model of depression

Emotional stress is considered a serious pathogenetic factor of depression. In this study an ultrasound model of emotional stress developed in our laboratory was applied. It is characterized by the use of ultrasound as the stressor agent. Animals are triggered not by any organic or physical disturbances but by the perception of adverse information. This type of stress can induce depressive-like behavioral changes in rodents, manifested by decreased sucrose preference and increased time of immobility in a forced swim test. Ultrasound stress also increased the levels of oxidative stress markers. This is important, as stress has an established association with increased oxidative processes in the central nervous system. Total glutathione and carbonyl protein content were selected as relevant brain markers, as glutathione plays a critical role in cellular defensive mechanisms during oxidative stress and the level of protein carbonyls can be a measure of global protein oxidation. We demonstrated that two weeks of chronic exposure to ultrasound was enough to cause depressive-like behavioral changes in rats. Increased levels of oxidative stress markers in the hippocampus and prefrontal cortex were also observed after two weeks of such stress. The current study has two goals: the first is to study the relationship of depression and oxidative stress; the second is an additional validation of our approach to modeling stress‑induced depressive-like states in rats. The present data further support the validity of the ultrasound model by expanding information related to the influence of ultrasound stress on behavioral and physiological parameters, which are of great importance in the development of stress-induced depression. A time correlation between the onset of symptoms and a change in the level of oxidative stress markers in the brain is also demonstrated.

Влияние кратковременного и длительного неконтролируемого стресса на животных доминантного и субординантного социального статуса с различным типом стрессорной реакции

The aim of this study was to explore the effects of the short-term and subchronic uncontrolled stress on the behavior of animals with different of coping styles and social status. The short-term stress (forced 5-minute swimming) inhibits locomotion in subordinate rats with passive coping style, while dominants with active coping style exhibit only a slight stress reaction (grooming). Under subchronic uncontrolled stress (4-hour immobilization in confined cases for 5 days), active dominants, but not passive subordinate rats, develop the signs of a depression-like state, such as decreased body weight, increased anhedonia and anxiety, increased locomotory and research activity, and increased pain threshold, on the 5-th day of exposure, compared to the background. The subordinate rats with passive coping style show the stress reaction marked by the decreased locomotory and research activity and increased anxiety on the 5-th day of exposure. Thus, short-term and subchronic uncontrolled stress have different effects on animals with opposite social status and coping styles. These data can be useful for individual selection of appropriate antidepressants based on psychophysiological characteristics.

Effects of Rimonabant on learning and memory of rats with olfactory bulbectomy

Olfactory bulbectomy (OBX) is an experimental model of depression, which has recently been used as a model of Alzheimer's disease due to the development of neurodegenerative changes in the brain. The OBX model in rodents is accompanied by biochemical, morphological and structural changes in the brain, as well as by many behavioral changes. A common finding in the OBX model are memory deficits, which are present in both depressive disorders and neurodegenerative diseases. There is evidence that the memory-impairing effect of cannabinoids is associated with activation of the cannabinoid CB1 receptors in the brain. The aim of the present study was to investigate the effects of the CB1 antagonist Rimonabant (SR 141716A) administered intragastrically daily for 14 days on the memory processes of OBX rats, tested in a passive avoidance (PA) paradigm. Rimonabant was administered to OBX rats, divided into three experimental groups: before OBX; immediately after OBX (1-14 days); with the presence of a depressive-like state (14-28 days after OBX). Rimonabant showed a tendency to improve the learning and memory of sham-operated controls, whereas no significant change in the behavioral responses was observed upon administration 14 days before OBX. However, Rimonabant, administered immediately after OBX completely prevented the development of memory deficit in a PA test, while its administration 14-28 days after OBX ameliorated the memory disturbances induced by bulbectomy. The results indicate that the CB1 antagonist Rimonabant may ameliorate the development of a memory deficit in OBX rats.

Perception and emotions: On the relationships between stress and olfaction

Adaptations to the ever changing social and physical environment are necessary, sometimes involving the stress response. Olfaction is a chemical sense allowing the detection of molecules in the air, and many species rely on it for social recognition and fundamental functions such as feeding or reproduction. This non-exhaustive literature review addresses three topics at the intersection of sensory biology and stress biology, in order to raise awareness and enlighten our understanding of animal behaviour. First, we show that stress and associated emotions, such as fear, can alter odour perception, from the sensor (peripheral nervous system) to the interpretation of the sensory input (brain). This can be of relevance for understanding the behavioural consequences of negative experiences and depression-like states. Second, odours involved in animal chemical communication can signal danger in the form of predators or stressed conspecifics, and in turn induce stress in recipient animals, as a form of chemical empathy. Finally, we review some of the evidence for the use of odours as stress-relief agents. There is no clear evidence of treatment efficacy and it might be that under the labels of inhalation aromatherapy, aromachology or pheromone therapy, a lack of perspective has led to the conflation of various biological phenomena: an alleged spontaneous olfactory effect on stress relief, environmental enrichment or the recall of positive emotional states. Careful experimental design and critical analysis are paramount to clearly evaluate this promising intervention. The world around us shapes our emotions, which in turn affect our perception. There might be a huge animal welfare potential to harvest from improved knowledge in the studies of stress and olfaction interactions, this will eventually allow us to show more empathy to animals in our care.

Curcumin relieves depressive-like behaviors via inhibition of the NLRP3 inflammasome and kynurenine pathway in rats suffering from chronic unpredictable mild stress

Increasing evidence suggests that inflammation is related to the pathophysiology of depression. Curcumin (CUR), which is a natural component extracted from the rhizome of Curcuma longa, seems to be efficacious in depression treatment. Hence, the present study aims to explore whether the anti-depressive effect of curcumin is connected to its anti-inflammatory features. Twenty-one SD rats were randomly divided into three groups, namely, control, CUMS (chronic unpredictable mild stress), and CUMS + CUR. After stress exposure for four weeks, the CUMS group showed depressive-like behaviors, and the curcumin treatment successfully corrected the depressive-like behaviors in stressed rats. Additionally, the curcumin could effectively decrease mRNA expression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and suppress NF-κB activation. Curcumin also inhibited the stressed-induced P2X7R/NLRP3 inflammasome axis activation, along with the reduced transformation of pro-IL-1β to mature IL-1β. The stress-induced activation of indolamine-2, 3-dioxygenase (IDO) and an increased kynurenine/tryptophan ratio were also ameliorated by curcumin supplementation. In conclusion, the study revealed that curcumin relieves a depressive-like state through the inhibition of the NLRP3 inflammasome and kynurenine pathway.

Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation

The neuropeptide dynorphin (DYN) activates kappa opioid receptors (KORs) in the brain to produce depressive-like states and decrease motivation. KOR-mediated suppression of dopamine release in the nucleus accumbens (NAc) is considered one underlying mechanism. We previously showed that, regardless of estrous cycle stage, female rats are less sensitive than males to KOR agonist-mediated decreases in motivation to respond for brain stimulation reward, measured with intracranial self-stimulation (ICSS). However, the explicit roles of KORs, circulating gonadal hormones, and their interaction with dopamine signaling in motivated behavior are not known. As such, we measured the effects of the KOR agonist U50,488 on ICSS stimulation thresholds before and after gonadectomy (or sham surgery). We found that ovariectomized females remained less sensitive than sham or castrated males to KOR-mediated decreases in brain stimulation reward, indicating that circulating gonadal hormones do not play a role. We used qRT-PCR to examine whether sex differences in gene expression in limbic brain regions are associated with behavioral sex differences. We found no sex differences in Pdyn or Oprk1 mRNA in the NAc and ventral tegmental area (VTA), but tyrosine hydroxylase (Th) mRNA was significantly higher in female compared to male VTA. To further explore sex-differences in KOR-mediated suppression of dopamine, we used fast scan cyclic voltammetry (FSCV) and demonstrated that U50,488 was less effective in suppressing evoked NAc dopamine release in females compared to males. These data raise the possibility that females are protected from KOR-mediated decreases in motivation by an increased capacity to produce and release dopamine.