Depression-related Behaviors Research Articles

Combined Extract of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi Improved Hot Flashes and Depression in an Ovariectomized Rat Model of Menopause.

Menopause leads to ovarian hormone loss, which causes symptoms such as weight gain, hot flashes, and depression. Exploring nutraceuticals is important for treating menopausal symptoms that extensively impact women’s quality of life. We hypothesized that a combination of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi (LEPE) would alleviate menopausal symptoms in an ovariectomized menopausal rat model. Bilateral ovariectomy was performed and animals were assigned to five groups: (1) Sham, (2) Vehicle, (-) Control, (3) LEPE (100 mg/kg bw), (4) LEPE (200 mg/kg bw), and (5) Estradiol (3 μg/kg bw). LEPE was orally administered daily for 12 weeks. LEPE supplementation did not affect growth performance (body weight and feed intake) or body composition (lean mass and fat in tissue). LEPE did not cause deviations in aspartate aminotransferase, alanine aminotransferase, estradiol, and follicle-stimulating hormone levels, indicating no hepatotoxicity or endocrine disturbance. LEPE decreased type I collagen (CTX-1) but did not affect bone mineral density or osteocalcin. LEPE decreased tail temperature and increased rectal temperature, improving menopause-related vasomotor symptoms. Furthermore, LEPE ameliorated depression-related behavior, including in forced swimming and tail suspension tests. Thus, LEPE may improve menopausal symptoms by enhancing vasomotor symptoms and depression in an ovariectomized rat menopause model.

Interaction between intensity and duration of acute exercise on neuronal activity associated with depression-related behavior in rats

We examined the activities of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) and corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) during acute treadmill running at different speeds (control, low, high) and durations (15, 30, 60 min) in male Wistar rats using c-Fos/5-HT or CRF immunohistochemistry. We also performed elevated plus maze test (EPM) and forced swim test (FST) after acute treadmill running in rats. Acute treadmill running at low speed, regardless of exercise duration, significantly increased c-Fos expression in 5-HT neurons in the DRN compared with controls, whereas high-speed running significantly activated 5-HT neurons only at 60-min duration. In contrast, c-Fos expression in CRF neurons in the PVN was enhanced in an intensity-dependent manner, regardless of exercise duration. c-Fos expression in 5-HT neurons in the DRN induced by the acute treadmill running for 30 or 60 min, but not 15 min, was positively correlated with the time spent on the open arms in the EPM and was negatively correlated with the immobility time in the FST. These results suggest an interaction between exercise intensity and duration on the antidepressant effects of acute physical exercise.

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.

When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment. Our data therefore suggest a Janus-faced dose-response curve for donepezil in depression-related behavior. In this review, we investigate the mood-related properties of AChEIs in greater detail, focusing on both human and rodent studies. In fact, while there have been many studies showing pro-depressant activity by AChEIs and this is a major concept in the field, a variety of other studies in both humans and rodents show antidepressant effects. Our study was one of the first to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant roles for AChEIs in rodents may provide hope for new depression treatments. Importantly, MDD is a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying depression mechanisms, so an important future direction will be to determine the extent to which these depression-related effects are stress-sensitive. In sum, gaining a greater understanding of the potentially therapeutic mood-related effects of low dose AChEIs, both in rodent models and in human subjects, should be a prioritized topic in ongoing translational research.

Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity

Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.

Striatal RGS7 Regulates Depression-Related Behaviors and Stress-Induced Reinstatement of Cocaine Conditioned Place Preference.

The striatum plays a key role in both reward-related and affective behaviors and disruptions to this circuit contributes to depression and drug addiction. However, our understanding of the molecular factors that facilitate and modify these processes are incomplete. Striatal function is modulated by G-protein-coupled receptors (GPCRs) that process vast neuromodulatory inputs. GPCR signaling is negatively regulated by regulator of G-protein signaling (Rgs) proteins. In this study, we examine the role of striatal Rgs proteins in depressive-like and reward-related behaviors in male mice. Using a genetic mouse model with specific elimination of Rgs7 in striatal neurons we found that these mice exhibit an anxiolytic-like and antidepressant-like phenotype. In contrast, knock-out of Rgs9, an abundant Rgs protein in the same neuronal population did not affect the behavioral outcome in the depressive-like tests. Mice lacking striatal Rgs7 did not show significant differences in cocaine-induced psychomotor activation, sensitization or conditional place preference (CPP). Interestingly, loss of Rgs7 in the striatum made mice resilient to stress-induced but not drug-induced reinstatement of cocaine CPP. Analysis of striatal proteome revealed that loss of Rgs7 selectively affected expression of several networks, most prominently including proteins involved in translation and vesicular exocytosis. Together, these findings begin to demonstrate the specific contribution of Rgs7 acting in the striatum toward depression as it relates to stress-induced reinstatement of drug use.

Intranasal Administration of Melanin-Concentrating Hormone Reduces Stress-Induced Anxiety- and Depressive-Like Behaviors in Rodents.

Major depressive disorder is a complex neuropsychiatric disorder with few treatment options. Non-targeted antidepressants have low efficacy and can induce series of side effects. While a neuropeptide, melanin-concentrating hormone (MCH), is known to exhibit regulator of affective state, no study to date has assessed the anti-depressive effects of MCH in a stress-induced depression model. This study aimed to evaluate the pharmacological effects of intranasal administration of MCH on depression-related behavior in stressed rats and mice. Using a number of behavioral tests, we found that MCH treatment significantly decreased anxiety- and depressive-like behaviors induced by stress. Notably, the effects of MCH were equivalent to those of fluoxetine. MCH treatment also restored the activity of the mammalian target of rapamycin (mTOR) signaling pathway and normalized the levels of synaptic proteins, including postsynaptic density 95, glutamate receptor 1, and synapsin 1, which were all downregulated by stress. Interestingly, the protective effects of MCH were blocked by the mTOR inhibitor, rapamycin. These results suggest that MCH exhibits antidepressant properties by modulating the mTOR pathway. Altogether, this study provides an insight into the molecular mechanisms involved in the antidepressant-like effects of MCH, thereby paving the way for the future clinical application of MCH.

Intracerebroventricular Administration of Interferon-Alpha Induced Depressive-Like Behaviors and Neurotransmitter Changes in Rhesus Monkeys.

Interferon-alpha (IFN-α) is a cytokine widely used in the treatment of brain cancers and virus infections with side effects including causing depression. Monoamine neurotransmitter systems have been found playing important roles in peripheral IFN-α-induced depression, but how peripheral IFN-α accesses the central nervous system and contributes to the development of depression is poorly known. This study aimed to develop a non-human primate model using long-term intracerebroventricular (i.c.v.) administration of IFN-α (5 days/week for 6 weeks), to observe the induced depressive-like behaviors and to explore the contributions of monoamine neurotransmitter systems in the development of depression. In monkeys receiving i.c.v. IFN-α administration, anhedonia was observed as decreases of sucrose consumption, along with depressive-like symptoms including increased huddling behavior, decreases of spontaneous and reactive locomotion in home cage, as well as reduced exploration and increased motionless in the open field. Chronic central IFN-α infusion significantly increased the cerebrospinal fluid (CSF) concentrations of noradrenaline (NA), and 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). These CSF monoamine metabolites showed associations with some specific depression-related behaviors. In conclusion, central IFN-α administration induced anhedonia and depression-related behaviors comparable to the results with peripheral administration, and the development of depression was associated with the dysfunction of monoamine neurotransmitters.

URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels.

Methamphetamine is an addictive stimulant that possesses toxicity in the brain when taken repeatedly or at higher doses. Methamphetamine neurotoxicity is associated with numerous forms of mental impairment, including depression and anxiety. Evidence has also demonstrated that the endocannabinoid system is involved in the regulation of anxiety and depression. This study was designed to determine the involvement of the endocannabinoid system in anxiety- and depression-related behaviors in methamphetamine-withdrawal male NMRI mice. The elevated plus maze and forced swim test were used to assess the level of anxiety and depression. We found that methamphetamine (30 mg/kg, intraperitoneal) evoked depressive- and anxiogenic-like effects at 3 days post-administration. Injection of URB597 (5-10 ng/mouse, intracerebroventricular), 10 min before the test, prevented the emotional deficits induced by methamphetamine withdrawal. Moreover, the cannabinoid receptor type 1 antagonist AM251 (1 μg/mouse) or cannabinoid receptor type 2 antagonist AM630 (5 and 10 μg/mouse) suppressed the antidepressant activity in the methamphetamine-withdrawal mice treated with URB597. The transient receptor potential vanilloid 1 antagonist capsazepine (25 μg/mouse) prevented while capsazepine (100 μg/mouse) potentiated the antidepressant efficacy in the methamphetamine-withdrawal mice treated with URB597. The higher dose of AM630 and two higher doses of capsazepine had antidepressant efficacy, by themselves. Furthermore, capsazepine (50 μg/mouse) increased locomotion in the methamphetamine-withdrawal mice treated with URB597. The results suggest that URB597 has a potential for preventing methamphetamine withdrawal-evoked anxiety and depression. Cannabinoid type 1 receptors, cannabinoid type 2 receptors and transient receptor potential vanilloid 1 differently affect depression-related behaviors in methamphetamine-withdrawal mice treated with URB597.

Xanthotoxin affects depression-related behavior and neurotransmitters content in a sex-dependent manner in mice

The present study aimed to evaluate xanthotoxin's influence on male and female Swiss mice's depression-like behaviors and investigate the potential mechanism of this effect. Naturally derived furanocoumarin (the Apiaceae family), xanthotoxin, administered acutely (12.5 mg/kg), diminished the immobility level in the forced swim test only in males. The immobility level was lower in females than males, which may be associated with a higher serotonin level in the female prefrontal cortex. A dose-dependent increase of serotonin and noradrenaline was reported in the reverse-phase ion-pair liquid chromatography in the female prefrontal cortex but not in the hippocampus. We suggest that xanthotoxin may exert antidepressant properties and affect males and females differently. The increasing level of serotonin in the male and female prefrontal cortex may underlie this effect.

Behavioural phenotyping of thunder mice with a hypomorphic mutation of heterogeneous nuclear ribonuclear protein L-like (hnRNPLL) and reduced T cell function

Heterogeneous nuclear ribonuclear protein l-like (hnRNPLL) is an RNA binding protein that regulates alternative splicing of mRNA and is abundantly expressed in memory T lymphocytes of the immune system and in the brain. A hypomorphic allele of the gene encoding hnRNPLL (Hnrpllthunder) selectively reduces T cell accumulation in lymphoid tissues, but little is known about its effects in the brain. Therefore, we exposed Hnrpllthunder mice to a test battery with relevance for a range of psychiatric illnesses. Thunder mice showed enhanced immobility in the tail-suspension test for depression-related behaviours, impaired short-term spatial memory in the Y-maze and reduced avoidance learning in the active avoidance test. Thus, in addition to its reported effects on immune function, the hnRNPLL mutation in thunder mice selectively affected aspects of behaviour.

Political depression? A big-data, multimethod investigation of Americans' emotional response to the Trump presidency.

Previous studies suggested that the 2016 presidential elections gave rise to pathological levels of election-related distress in liberal Americans; however, it has also been suggested that the public discourse and the professional discourse have increasingly overgeneralized concepts of trauma and psychopathology. In light of this, in the current research, we utilized an array of big data measures and asked whether a political loss in a participatory democracy can indeed lead to psychopathology. We observed that liberals report being more depressed when asked directly about the effects of the election; however, more indirect measures show a short-lived or nonexistent effect. We examined self-report measures of clinical depression with and without a reference to the election (Studies 1A & 1B), analyzed Twitter discourse and measured users' levels of depression using a machine-learning-based model (Study 2), conducted time-series analysis of depression-related search behavior on Google (Study 3), examined the proportion of antidepressants consumption in Medicaid data (Study 4), and analyzed daily surveys of hundreds of thousands of Americans (Study 5), and saw that at the aggregate level, empirical data reject the accounts of "Trump Depression." We discuss possible interpretations of the discrepancies between the direct and indirect measures. The current investigation demonstrates how big-data sources can provide an unprecedented view of the psychological consequences of political events and sheds light on the complex relationship between the political and the personal spheres. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons.

Pharmacological studies have implicated the translocator protein (TSPO) in the regulation of complex behaviors including anxiety and depression, effects thought to be mediated by increased synthesis of neuroactive steroid hormones. However, TSPO function in the brain remains to be corroborated in vivo via genetic studies. To address this, we developed global TSPO knockout (TSPO-KO) and neuronal TSPO transgenic (TSPO-Tg) mouse models to investigate TSPO function in the regulation of anxiety- and depression-related behaviors using elevated plus maze and forced swim test paradigms. Neuroactive steroid hormones were measured in the brain by mass spectrometry. In vivo TSPO ligand pharmacokinetics was investigated using competitive PET with 18F-FE-DAA1106. Genetic TSPO deficiency increased anxiety-related behavior and impaired brain steroidogenesis but did not affect depressive behaviors. Using the TSPO-KO model, we then demonstrated the specificity of Ac-5216, also known as XBD-173 or Emapunil, as an anxiolytic targeting TSPO at doses optimized by competitive PET for high cortical occupancy. Neuronal TSPO overexpression decreased depressive behaviors, an effect that was dependent on steroidogenesis, and partially reversed anxiogenic behavior in TSPO-KO mice. These findings demonstrate that TSPO is critical for brain steroidogenesis and modulates anxiety- and depression-related behaviors. However, we demonstrate that key differences in the contribution of neuronal TSPO to the modulation of these complex behaviors, illustrating the tissue- and cell-specific importance of TSPO. The TSPO-KO and TSPO-Tg mice provide the tools and rationale for the development of therapeutic approaches targeting TSPO in the brain for treatment of neuropsychiatric conditions.

Effect and mechanism of high-fat diet on the preference for sweeteners on mice.

Male Kunming mice were divided into a normal diet group (control group) and a high-fat diet group (HF group) (185 g·kg-1 protein, 600 g·kg-1 fat and 205 g·kg-1 carbohydrate). After 8 weeks' feeding, behavioral indicators and biochemical indicators in serum were determined. The double-bottle preference experiment was used to study the preferences of mice for five sweeteners. The monoamine neurotransmitter content, gene expression related to dopamine (DA), and opioid receptors were also determined. The body weight of the mice in the HF group increased significantly (P < 0.05) after 36 days compared with the control group. The feed intake of the HF group increased sharply in the first 12 days, and then it became basically unchanged. The preference of the HF group for all of the five sweeteners was highly significantly lower (P < 0.01) than that of the control group. Depression-related behavior was observed in the HF group mice. The triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDLC) content in the HF group were very much higher (P < 0.01) than those of the control group. The gene expression related to DA and opioid receptor in the HF group was significantly lower than that of the control group, except for preproenkephalin (PENK). In summary, this study suggested that a long-term high-fat diet could result in a decrease in the preference for sweeteners and could result in a state of reward hypofunction in mice. © 2020 Society of Chemical Industry.

Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats.

In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ1) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3. To evaluate the effect of the increase in the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at the σ1 receptor significantly higher than that of the lead compound 1. In particular, 3 displayed unprecedented selectivity over the σ2 receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over the dopamine transporter. Docking results supported the structure–activity relationship studies. Due to its interesting biological profile, derivative 3, selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of the σ1 receptor in the compulsive-like eating behavior and supported the σ1 receptor as a promising target for the management of eating disorders.

Dopamine D4 receptors in the lateral habenula regulate depression-related behaviors via a pre-synaptic mechanism in experimental Parkinson's disease

Although multiple studies report that unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induce depressive-like behaviors and hyperactivity of the lateral habenula (LHb), effects of dopamine (DA) D4 receptors in the LHb on depressive-like behaviors are unclear. Here we found that intra-LHb injection of the different doses of D4 receptor agonist A412997 and antagonist L741742 produced the different behavioral responses in SNc sham-lesioned rats, and only the high doses of A412997 and L741742 increased the expression of depressive-like behaviors or produced antidepressant-like effects in SNc-lesioned rats. The low doses of A412997 and L741742 altered the firing rate of LHb neurons and release of DA, GABA and glutamate in the LHb via the GABAergic rostromedial tegmental nucleus (RMTg) in SNc sham-lesioned rats, but not in SNc-lesioned rats. The high doses of A412997 and L741742 also altered the firing rate and release of the transmitters in both SNc sham-lesioned and SNc-lesioned rats, whereas these effects were not involved in the RMTg. Lesions of the SNc shortened the duration of significant effects on the firing rate and release of the transmitters induced by the high doses of A412997 and L741742. These findings suggest that D4 receptors in the LHb are involved in depression-like behaviors via the pre- and post-synaptic mechanisms and depletion of DA decreases the function and/or the expression of both pre- and post-synaptic D4 receptors. This study also points to the importance of the pre-synaptic D4 receptors in the regulation of Parkinson's disease-related depression.

Diacylglycerol lipase alpha in astrocytes is involved in maternal care and affective behaviors.

Genetic deletion of cannabinoid CB1 receptors or diacylglycerol lipase alpha (DAGLa), the main enzyme involved in the synthesis of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG), produced profound phenotypes in animal models of depression-related behaviors. Furthermore, clinical studies have shown that antagonists of CB1 can increase the incidence and severity of major depressive episodes. However, the underlying pathomechanisms are largely unknown. In this study, we have focused on the possible involvement of astrocytes. Using the highly sensitive RNAscope technology, we show for the first time that a subpopulation of astrocytes in the adult mouse brain expresses Dagla, albeit at low levels. Targeted lipidomics revealed that astrocytic DAGLa only accounts for a minor percentage of the steady-state brain 2-AG levels and other arachidonic acid derived lipids like prostaglandins. Nevertheless, the deletion of Dagla in adult mouse astrocytes had profound behavioral consequences with significantly increased depressive-like behavioral responses and striking effects on maternal behavior, corresponding with increased levels of serum progesterone and estradiol. Our findings therefore indicate that lipids from the DAGLa metabolic axis in astrocytes play a key regulatory role in affective behaviors.

Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice.

IntroductionThe two‐pore domain potassium channel TREK‐1 is a member of background K+ channels that are thought to provide baseline regulation of membrane excitability. Recent studies have highlighted the putative role of TREK‐1 in the action of antidepressants, and its antagonists might be potentially effective antidepressants. However, the mechanisms underlying the actions of TREK‐1 are not yet fully understood.MethodsThe expression of TREK‐1 was examined in a mouse model of chronic unpredictable mild stress (CUMS) using immunoblotting. Neuron‐specific genetic manipulation of TREK‐1 was performed through adeno‐associated virus. Behavioral tests were performed to evaluate depression‐related behaviors. Electrophysiological recordings were used to evaluate synaptic plasticity. Golgi staining was used to examine neuroplasticity.ResultsTREK‐1 expression was increased in the mouse hippocampus after CUMS. Knockdown of TREK‐1 in hippocampal neurons significantly attenuated depressive‐like behaviors and prevented the decrease of CUMS‐induced synaptic proteins in mice. Further examination indicated that neuron‐specific knockdown of TREK‐1 in the hippocampus prevented stress‐induced impairment of glutamatergic synaptic transmission in the CA1 region. Moreover, chronic TREK‐1 inhibition protected against CUMS‐induced depressive‐like behaviors and impairment of synaptogenesis in the hippocampus.ConclusionOur results indicate a role for TREK‐1 in the modulation of synaptic plasticity in a mouse model of depression. These findings will provide insight into the pathological mechanism of depression and further evidence for a novel target for antidepressant treatment.

Long-term exercise from adolescence to adulthood reduces anxiety- and depression-like behaviors following maternal immune activation in offspring

Maternal immune activation is an environmental risk factor for the development of neuropsychiatric disorders such as anxiety and depression later in life. There is an urgent need to develop therapeutic strategies for treating or preventing psychiatric disorders with developmental origins. There is important information that physical exercise is a therapeutic strategy for treating anxiety and depression-related disorders. This study set out to determine the long-term effects of exercise on anxiety and depression-like behaviors following maternal immune activation in adult offspring. Pregnant mice were treated with lipopolysaccharides (LPS) or vehicle. Then offspring were subjected to a combination of different exercise protocols including voluntary running wheel, swimming, and treadmill exercises from adolescence to adulthood. Anxiety and depression-related symptoms in adult offspring were evaluated using open field, elevated plus maze, sucrose preference test, and forced swim test. The hypothalamic–pituitary–adrenal (HPA) axis reactivity was assessed by measuring corticosterone in serum. We also measured oxytocin, malondialdehyde, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in the brain of adult offspring. Our findings indicated that long-term exercise significantly decreased anxiety- and depression-like behaviors in offspring prenatally exposed to maternal immune activation. The exercise also decreased corticosterone levels in the serum, and increased oxytocin and IL-10 levels in the brain of these offspring; whereas no significant alterations in TNF-α, IL-1β, IL-6 were found. Taken together, this study suggests that exercise might be a therapeutic strategy for the treatment of anxiety and depression-related behaviors following maternal immune activation in offspring.

Potassium-dependent sodium/calcium exchanger 3 (Nckx3) depletion leads to abnormal motor function and social behavior in mice.

Transcellular calcium transport is an essential activity in mineralized tissue formation, including that in nervous systems. Dysregulation of Ca2+ homeostasis can induce excitotoxicity and neurodegeneration in the central nervous system. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is most abundant in the brain and has a critical role in the transport of intracellular calcium across the cell membrane. However, the roles of Nckx3 in neuron development and function remain unreported. Herein, we examined the behaviors of Nckx3-knock-out mice at the age of six weeks. Detailed behavioral analyses showed Nckx3-/- mice exhibited an increase in moving distances in the open field test. Additionally, the rotarod test revealed motor learning defects in Nckx3-/- mice. Both Nckx3+/- and Nckx-/- mice also exhibited deficits in sociability and social novelty preference. Furthermore, Nckx-/- mice displayed increased depression-related behavior. However, there was no significant change in cognition function detected in Nckx-/- mice. This study demonstrates that NCKX3 is involved in behavior and neuronal function.

The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test

Finding new antidepressant agents is of high clinical priority given that many cases of major depressive disorder (MDD) do not respond to conventional monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Recent findings of effective fast-acting antidepressants indicate that there are biological substrates to be taken advantage of for fast relief of depression and that we may find further treatments in this category. In this vein, the cholinergic system may be a relatively overlooked target for antidepressant medications, given its major role in motivation and attention. Furthermore, the classically engaged monoaminergic neurotransmitter systems in depression treatment—serotonin, norepinephrine, and dopamine—interact directly at times with cholinergic signaling. Here we investigate in greater detail how the cholinergic system may impact depression-related behavior, by administering widely ranging doses of the cholinesterase inhibitor drug, donepezil, to C57BL/6J mice in the forced swim test. First, we confirm prior findings that this drug, which is thought to boost synaptic acetylcholine, promotes depression-like behavior at a high dose (2.0 mg/kg, i.p.). But we also find paradoxically that it has an antidepressant-like effect at lower doses (0.02 and 0.2 mg/kg). Further this antidepressant-like effect is not due to generalized hyperactivity, since we did not observe increased locomotor activity in the open field test. These data support a novel antidepressant-like role for donepezil at lower doses as part of an overall u-shaped dose-response curve. This raises the possibility that donepezil could have antidepressant properties in humans suffering from MDD.