Urocanic acid enhances memory consolidation and reconsolidation in novel object recognition task.

Urocanic acid (UCA) is an endogenous small molecule that is elevated in skin, blood and brain after sunlight exposure, mainly playing roles in the periphery systems. Few studies have investigated the role of UCA in the central nervous system. In particular, its role in memory consolidation and reconsolidation is still unclear. In the present study, we investigated the effect of intraperitoneal injection of UCA on memory consolidation and reconsolidation in a novel object recognition memory (ORM) task. In the consolidation version of the ORM task, the protocol involved three phases: habituation, sampling and test. UCA injection immediately after the sampling period enhanced ORM memory performance; UCA injection 6 h after sampling did not affect ORM memory performance. In the reconsolidation version of the ORM task, the protocol involved three phases: sampling, reactivation and test. UCA injection immediately after reactivation enhanced ORM memory performance; UCA injection 6 h after reactivation did not affect ORM memory performance; UCA injection 24 h after sampling without reactivation did not affect ORM memory performance. This UCA-enhanced memory performance was not due to its effects on nonspecific responses such as locomotor activity and exploratory behavior. The results suggest that UCA injection enhances consolidation and reconsolidation of an ORM task, which further extends previous research on UCA effects on learning and memory.

Chronic administration of parecoxib exerts anxiolytic-like and memory enhancing effects and modulates synaptophysin expression in mice.

BACKGROUND: Previous studies have shown that cyclooxygenase-2, a key enzyme that converts arachidonic acid to prostaglandins, is involved in anxiety and cognitive processes, but few studies have investigated the effects of chronic administration of cyclooxygenase-2 inhibitors on anxiety, learning and memory under normal physiological conditions. The aim of the study was to investigate the effects of chronic administration of parecoxib, a cyclooxygenase-2 inhibitor, on anxiety behavior and memory performance under normal physiological conditions and to explore the possible neural mechanism underlying parecoxib-mediated effects. METHODS: Adult male ICR mice were randomly divided into four groups: the control group and three parecoxib groups. Mice received normal saline or parecoxib (2.5, 5.0 or 10 mg/kg) intraperitoneal injection once a day for 21 days, respectively. Elevated plus-maze, novel object recognition and Y maze tests were conducted on day 23, 24 and 26, respectively. Four additional groups that received same drug treatment were used to measure synaptophysin protein levels by western blot and prostaglandin E2 (PGE2) levels by ELISA in the amygdala and hippocampus on day 26. RESULTS: Chronic parecoxib exerted an anxiolytic-like effect in the plus-maze test test, and enhanced memory performance in the novel object recognition and Y maze tests. Western blot analysis showed that chronic parecoxib down-regulated synaptophysin levels in the amygdala and up-regulated synaptophysin levels in the hippocampus. ELISA assay showed that chronic parecoxib inhibited PGE2 in the hippocampus but not amygdala. CONCLUSIONS: Chronic parecoxib exerts anxiolytic-like and memory enhancing effects, which might be mediated through differential modulation of synaptophysin and PGE2 in the amygdala and hippocampus.

Apelin-13 Impaires Acquisition but Not Consolidation or Expression of Contextual Fear in Rats.

Apelin-13, as an endogenous neuropeptide, is the ligand for the G-protein-coupled receptor, APJ, which has recently been demonstrated to be involved in the process that contributes to learning and memory. Previous studies showed that apelin may be required for certain forms of learning and memory. Up to date, the role of apelin in fear memory has not been explored. In the present study, we tested the effects of apelin-13 (1.0, 2.0 and 4.0 µg/rat) on contextual fear conditioning (experiment 1), consolidation (experiment 2) and expression (experiment 3) in rats. A well established fear conditioning protocol was used, which contained three training phases: habituation, fear conditioning and test. Apelin-13 was i.c.v injected 10 min before conditioning (experiment 1), immediately after conditioning (experiment 2) or 10 min before testing (experiment 3). The values of percent freezing were used to measure fear. We found that only 2.0 µg apelin-13 administrations produced a decrease freezing in experiment 1. The most effective dose of apelin-13 (2.0 µg) was selected, but it had no effect on freezing in experiment 2 and 3. Furthermore, the decreased freezing in experiment 1 was not attributed to the deficits of locomotor activity and foot-shock sensitivity. These results, for the first time, indicated that apelin-13 impaired fear acquisition but not fear consolidation or expression.

Apelin-13 Protects PC12 Cells from Corticosterone-Induced Apoptosis Through PI3K and ERKs Activation.

It is widely accepted that environmental stress is a risk factor for mental disorders. Glucocorticoid hormones play a vital role in the regulation of physiological response to stress. High concentrations of corticosterone can induce cellular damage in PC12 cells, which possess typical neuronal features. Apelin and its receptor APJ are widely distributed in the central nervous system including limbic structures involved in stress responses. Previous studies have suggested that apelin has a neuroprotective function. However, the effect of apelin on corticosterone-induced neuronal damage remains to be elucidated. In the present study, we explored the potential protective activity of apelin-13 in PC12 cells treated with corticosterone and its underling mechanisms. The viability of the cells, the apoptosis of the cells, the level of phosphorylation of Akt (p-Akt) and extracellular signal-regulated kinases (p-ERKs) and cleaved caspase-3 expression were detected by MTT, Hoechst staining and flow cytometer assays and Western blotting. Results showed that corticosterone induced cells viability loss, cell apoptosis, down-regulation of p-Akt and p-ERKs and up-regulation of cleaved caspase-3. The effects induced by corticosterone were attenuated by apelin-13 pretreatment. Furthermore, apelin-13-mediated anti-viability loss, antiapoptosis and caspase-3 suppression activities were blocked by specific inhibitors of phosphatidylinositol 3-kinase (PI3K) (LY294002) and ERKs (PD98059). The data suggest that apelin-13 protects PC12 cells from corticosterone-induced apoptosis through activating PI3K/Akt and ERKs signaling pathways.

Apelin-13 Prevents the Delayed Neuropathy Induced by Tri-ortho-cresyl Phosphate Through Regulation the Autophagy Flux in Hens.

Organophosphate-induced delayed neuropathy (OPIDN) is pathologically characterized by the swollen axon containing aggregations of microtubules, neurofilaments, smooth endoplasmic reticulum and multivesicular vesicles. At present, the exact mechanism of OPIDN is unclear and the effective therapeutic methods is not available to counter this syndrome. Recent studies had shown that the autophagy was involved in OPIDN. The adipocytokine Apelin is a peptide, Apelin and its receptor are abundantly expressed in the nervous system. Recent researches illuminated that Apelin was neuroprotective factor and Apelin could regulate the autophagy in vivo and vitro model. So we investigated the effect of Apelin-13 on the OPIDN induced by Tri-ortho-cresyl phosphate (TOCP) in hens and explored the role of autophagy in Apelin-13 preventing OPIDN. Adult Roman hens were given a single dose of 750 mg/kg TOCP by gavage for 21 days to induce OPIDN, and neural dysfunction were detected, and the formation of autophagosomes in spinal cord neurons was observed by transmission electron microscopy, and the molecular markers of autophagy microtubule-associated protein light chain-3 (LC3) and the autophagy substrates p62/SQSTM1 were determined by Western blot analysis. The results demonstrated that the obvious neurological dysfunction such as hindlimb paralysis and paralysis of gait was present, the number of autophagosomes in the neurons of spinal cords was significantly increased, the level of LC3-II and p62 expressions and the ratio of LC3-II/LC3-I in spinal cords and sciatic nerve were significantly increased in the OPIDN model group compared with the control group. Compared with the OPIDN model group, the neurological dysfunction of tens was obviously reduced, the clinical signs scores was significantly decreased, the number of autophagosomes in the neurons of hen spinal cords was significantly decreased, the level of LC3-II and p62 expressions and the ratio of LC3-II/LC3-I in spinal cords and sciatic nerve were significantly decreased in Apelin-13 treatment group. Our results suggested that Apelin-13 prevented against the OPIDN induced by TOCP in hens, which the mechanism might be associated with regulation autophagy flux by Apelin-13.

Acute Administration of Lactate Exerts Antidepressant-like Effect Through cAMP-dependent Protein Synthesis.

Lactate acts as an important metabolic substrate and signalling molecule modulating neural activities in the brain, and recent preclinical and clinical studies have revealed its antidepressant effect after acute or chronic peripheral administration. However, the neural mechanism underlying the antidepressant effect of lactate, in particular when lactate is acutely administered remains largely unknown. In the current study, we focused on forced swimming test (FST) to elucidate the neural mechanisms through which acute intracerebroventricular (ICV) infusion of lactate exerts antidepressant-like effect. A total of 238 male Sprague Dawley rats were used as experimental subjects. Results showed lactate produced antidepressant-like effect, as indicated by reduced immobility, in a dose- and time-dependent manner. Moreover, the antidepressant-like effect of lactate was dependent of new protein synthesis but not new gene expression, lactate's metabolic effect or hydroxy-carboxylic acid receptor 1 (HCAR1) activation. Furthermore, lactate rapidly promoted dephosphorylation of eukaryotic elongation factor 2 (eEF2) and increased brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus in a cyclic adenosine monophosphate (cAMP)-dependent manner. Finally, inhibition of cAMP production blocked the antidepressant-like effect of lactate. These findings suggest that acute administration of lactate exerts antidepressant-like effect through cAMP-dependent protein synthesis.

A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' disease.

Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Aß-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Aß(1-42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Aß(1-42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD.

How Oxidative Stress Induces Depression?

Depression increasingly affects a wide range and a large number of people worldwide, both physically and psychologically, which makes it a social problem requiring prompt attention and management. Accumulating clinical and animal studies have provided us with substantial insights of disease pathogenesis, especially central monoamine deficiency, which considerably promotes antidepressant research and clinical treatment. The first-line antidepressants mainly target the monoamine system, whose drawbacks mainly include slow action and treatment resistant. The novel antidepressant esketamine, targeting on central glutamatergic system, rapidly and robustly alleviates depression (including treatment-resistant depression), whose efficiency is shadowed by potential addictive and psychotomimetic side effects. Thus, exploring novel depression pathogenesis is necessary, for seeking more safe and effective therapeutic methods. Emerging evidence has revealed vital involvement of oxidative stress (OS) in depression, which inspires us to pursue antioxidant pathway for depression prevention and treatment. Fully uncovering the underlying mechanisms of OS-induced depression is the first step towards the avenue, thus we summarize and expound possible downstream pathways of OS, including mitochondrial impairment and related ATP deficiency, neuroinflammation, central glutamate excitotoxicity, brain-derived neurotrophic factor/tyrosine receptor kinase B dysfunction and serotonin deficiency, the microbiota-gut-brain axis disturbance and hypothalamic-pituitary-adrenocortical axis dysregulation. We also elaborate on the intricate interactions between the multiple aspects, and molecular mechanisms mediating the interplay. Through reviewing the related research progress in the field, we hope to depict an integral overview of how OS induces depression, in order to provide fresh ideas and novel targets for the final goal of efficient treatment of the disease.

Apelin-13 reduces lipopolysaccharide-induced neuroinflammation and cognitive impairment via promoting glucocorticoid receptor expression and nuclear translocation.

Neuroinflammation is usually associated with cognitive decline, which is involved in neurodegenerative diseases. Apelin, a neuropeptide, exerts various biological roles in central nervous system. Recent evidence showed that apelin-13, an active form of apelin, suppresses neuroinflammation and improves cognitive decline in diverse pathological processes. However, the underlying mechanism of apelin-13 in neuroinflammation remains largely unknown. The present study aimed to determine underlying mechanism of apelin-13 on neuroinflammation-related cognitive decline. The lipopolysaccharide (LPS) intracerebroventricular (i.c.v.) to is used to establish a rat model of neuroinflammation-related cognitive decline. The results showed that apelin-13 inhibits LPS-induced neuroinflammation and improves cognitive impairment. Apelin-13 upregulates the GR level and nuclear translocation in hippocampus of rats. Moreover, glucocorticoid receptor inhibitor RU486 prevents apelin-13-mediated neuroprotective actions on cognitive function. Taken together, apelin-13 could exert a protective effect in neuroinflammation-mediated cognitive impairment via the activation of GR expression and nuclear translocation.

[Glycogen phosphorylase inhibitor ameliorates pentylenetetrazole-induced acute seizure, neuroinflammation and memory impairment in rats].

OBJECTIVE: In the present study, we determined whether the glycogen phosphorylase(GP)inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) ameliorates pentylenetetrazole (PTZ)-induced acute seizure, neuroinflammation and memory impairment in rats. METHODS: In experiment 1, rats were randomly divided into the Vehicle (n=5) and PTZ (n=5) groups, and received intraperitoneal injection of saline or PTZ (70 mg/kg), respectively. Hippocampal tissues were collected 30 min after drug injection. Western blot was used to examine the levels of GP expression. Colorimetric assay was used to determine the levels of lactate. In experiment 2, rats were randomly divided into the Vehicle+Vehicle (n=18), DAB+Vehicle (n=18), Vehicle+PTZ (n=19) and DAB+PTZ (n=18) groups. Rats received intracerebroventricular injection of PBS or DAB (50 µg/2 µl) 15 min before receiving intraperitoneal injection of saline or PTZ (70 mg/kg). Behavioural assays and the Racine scale were used to evaluate seizure severity. Western blot was used to examine the levels of targeted protein of hippocampal tissues. Novel object recognition test was used to assess memory performance. RESULTS: ① Compared with the Vehicle group, the levels of GP and lactate in the hippocampal tissues of the PTZ group were increased significantly (both P＜0.01). ② Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of myoclonic body jerk latency, forelimb clonus latency and tonic-clonic seizure latency were increased significantly (all P＜0.01), while the duration of seizure and seizure scores were decreased significantly (both P＜0.01). ③ Compared with the Vehicle+Vehicle group, in the Vehicle +PTZ group, the levels of IL-1ß, IL-6, TNF-α, IBA-1 and GFAP in the hippocampal tissues were increased significantly (all P＜0.01), and the discrimination index in the novel object recognition test was decreased significantly (P＜0.01). Compared with the Vehicle+PTZ group, in the DAB+PTZ group, the levels of IL-1ß, TNF-α, IBA-1 and GFAP in the hippocampal tissues were decreased significantly (all, P＜0.01), while the discrimination index in the novel object recognition test was increased significantly (P＜0.01). CONCLUSION: DAB ameliorates PTZ-induced seizure, neuroinflammation and memory impairment in rats, suggesting that DAB may serve as a novel agent for potential clinical treatment of epilepsy.

[Chronic nicotine enhances contextual fear memory in rats].

OBJECTIVE: To evaluate the effect of chronic nicotine on contextual fear memory in rats. METHODS: Rats were subcutaneously injected saline or nicotine for 14 days continuously to induce nicotine dependence. Somatic signs of spontaneous nicotine withdrawal were assessed on day 1 and 14 after the last injection. Locomotor activity was tested 13 days after the last injection. Contextual fear conditioning task was run 14 days after the last injection, which included 3 phases: habituation, fear conditioning, and test. Percent freezing was used as an index for fear memory during the conditioning and test phases. Finally, footshock sensitivity test was conducted. RESULTS: Compared with the saline group, the global withdrawal scores significantly increased in the nicotine group when the somatic signs were assessed 1 day after the nicotine injection, while there was almost no difference in the 2 groups 14 days after the last injection. In the contextual task, the nicotine group showed a significant increase in the level of freezing response during the test phase but not in the conditioning phase. There was no significant difference in the locomotor activity and footshock sensitivity between the 2 groups. CONCLUSION: Chronic nicotine enhances the contextual fear memory in rats. This effect is not attributed to the change of somatic signs, locomotor activity or footshock sensitivity.

Neuroprotective gain of Apelin/APJ system.

Apelin is an endogenous ligand of G protein-coupled receptor APJ. In recent years, many studies have shown that the apelin/APJ system has neuroprotective properties, such as anti-inflammatory, anti-oxidative stress, anti-apoptosis, and regulating autophagy, blocking excitatory toxicity. Apelin/APJ system has been proven to play a role in various neurological diseases and may be a promising therapeutic target for nervous system diseases. In this paper, the neuroprotective properties of the apelin/APJ system and its role in neurologic disorders are reviewed. Further understanding of the pathophysiological effect and mechanism of the apelin/APJ system in the nervous system will help develop new therapeutic interventions for various neurological diseases.

Ketamine enhances novel object recognition memory reconsolidation via the BDNF/TrkB pathway in mice.

In addition to the antidepressant properties of ketamine at subanesthetic doses, studies have revealed ketamine's influence on memory acquisition, consolidation, and reconsolidation. The effects of acute low-dose ketamine administration on conditioned memory have been investigated extensively in rodents through conditioned fear memory and morphine-induced conditioned place preference. In contrast to conditioned memory, the novel object recognition (NOR) task assesses the natural format of memory by exploiting the rodents' natural preference for novelty. Acute low-dose ketamine administration impairs NOR acquisition and consolidation, but its influence on reconsolidation remains unclear. We investigated the issue as well as the involvement of BDNF/TrkB pathway in this process by administering ketamine (i.p., 10 mg/kg, immediately or 6 h after reactivation, or without reactivation) and ANA-12 (i.p., 0.5 mg/kg, 5 min after ketamine/vehicle administration). ANA-12 is a selective antagonist for the BDNF TrkB receptor. Ketamine administration, immediately after (rather than without) reactivation, significantly increased the NOR preference index, thus suggesting an enhanced memory reconsolidation rather than consolidation. Ketamine exerted no significant effect when administered 6 h after reactivation, thereby suggesting 6 h to be an effective time window. ANA-12 administration significantly reduced the ketamine-induced NOR preference index increase, thus suggesting that the blockage of ketamine improves NOR reconsolidation. However, this blockage had no significant effect on the ketamine-induced hippocampal BDNF level increase. In conclusion, acute low-dose ketamine administration improves NOR memory reconsolidation by increasing hippocampal BDNF levels and subsequent BDNF binding to the TrkB receptor.

Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models.

AIM: To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice. METHODS: In the learned helplessness test (LH), Neu-P11 or melatonin (25-100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25-100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25-100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed. RESULTS: In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon. CONCLUSION: The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.

Apelin-13 enhances contextual fear extinction in rats.

Fear extinction is considered as a new learning process that is valid to model features of post-traumatic stress disorder (PTSD). The neuropeptide apelin, such as apelin-13, apelin-17 and apelin-36, are endogenous ligands of the G-protein coupled receptor APJ. Apelin and its receptor APJ are widely distributed in the central nervous system. Accumulating evidence suggests the critical role of apelin-13 in modulation of learning and memory, however, its specific role in fear extinction remains unclear. In the present study, we investigated the effect of apelin-13 administration on contextual fear extinction in rats. The behavioral procedure included four sessions: habitation, conditioning, extinction training and extinction recall. Rats received intracerebroventricular infusion of apelin-13 (3 or 6 µg) 0.5 h prior to the extinction training. Percentage of freezing was utilized to assess the conditioned fear response. Results showed that apelin-13, with the dose of 6 but not 3 µg, significantly decreased freezing response during both extinction training and extinction recall test sessions. Furthermore, apelin-13 did not affect the levels of baseline freezing, locomotor activity and anxiety. The results suggest that apelin-13 dose-dependently enhances contextual fear extinction, and may function as a novel target for treatment of PTSD.

Apelin-13 ameliorates chronic water-immersion restraint stress-induced memory performance deficit through upregulation of BDNF in rats.

A large number of studies have demonstrated that the hippocampus has important influences on stress response and memory. The abundant expressions of apelin and its receptor APJ in the hippocampus may imply potential involvement of apelin/APJ signaling in modulating stress-related memory performance deficit. In our previous study, apelin-13 ameliorates memory performance deficit in acute stressed rats. Here, we further examined whether apelin-13 can ameliorate memory performance deficit in chronic stressed rats. Rats were exposed to chronic water-immersion restraint stress (CWIRS) for 4 weeks. After stress withdrawal, apelin-13 was intracerebroventricularly infused once a day for one week. The novel object recognition test (NORT) and Y-maze test (YMT), two hippocampus-dependent memory tasks, were performed to assess memory performance. We found that apelin-13 restored CWIRS-induced decline in the discrimination index and alternation ratio in NORT and YMT, respectively. Furthermore, apelin-13 ameliorated CWIRS-induced hippocampal BDNF expression deficit, and the TrkB receptor antagonist ANA-12 blocked the ameliorative effect of apelin-13 on memory performance deficit in CWIRS rats. The current observations indicate that apelin-13 ameliorates CWIRS-induced memory performance deficit through upregulation of BDNF in rats.

Glutamate transporter GLT1 inhibitor dihydrokainic acid impairs novel object recognition memory performance in mice.

Glutamate transporter GLT1 mediates glutamate uptake, and maintains glutamate homeostasis in the synaptic cleft. Previous studies suggest that blockade of glutamate uptake affects synaptic transmission and plasticity. However, the effect of GLT1 blockade on learning and memory still receives little attention. In the present study, we examined the effect of unilateral intracerebroventricular injection of dihydrokainic acid (DHK), a GLT-1 inhibitor, on novel object recognition (NOR) memory performance. The NOR task involved three sessions including habituation, sampling and test. In experiment 1, DHK injection 0.5 h pre-sampling impaired short-term NOR memory performance. In experiment 2, DHK injection 0.5 h pre-sampling impaired long-term NOR memory acquisition. In experiment 3, DHK injection immediately but not 6 h post-sampling impaired long-term NOR memory consolidation. In experiment 4, DHK injection 0.5 h pre-test impaired long-term NOR memory retrieval. Furthermore, DHK-induced memory performance impairment was not due to its effects on nonspecific responses such as locomotor activity and exploratory behavior. The current findings further extend previous studies on the effects of disruption of glutamate homeostasis on learning and memory.

Apelin attenuates depressive-like behavior and neuroinflammation in rats co-treated with chronic stress and lipopolysaccharide.

Several experimental studies have proved that activation of neuroinflammation pathways may contribute to the development of depression, a neuropsychiatric disorder disease. Our previous studies have shown the antidepressant properties of apelin, but the mechanism was unkown. This study was performed to verify whether the antidepressant effect of apelin was related to its anti-inflammation effect in the central nervous system. To achieve our aim, we selected the co-treatment of chronic stress and LPS to induced an inflammatory process in rats. The effect of this co-treatment was evaluated through the expression of inflammatory markers and glial cell activation. LPS injection co-treated with unpredictable chronic mild stress resulted in the activation of microglial cell and astrocyte, expression of inflammatory markers and depressive behaviors. Treatment with apelin significantly attenuates the deleterious effects in these rats. Our results showed that apelin improved depressive phenotype and decreased the activation of glial cells in stress co-treatment group. The down-regulations of p-NF-κB and p-IKKß suggested that the effects are possibly mediated by inhibition of the NF-κB-mediated inflammatory response. These findings speculated that intracerebroventricular injection of apelin could be a therapeutic approach for the treatment of depression, and the antidepressant function of apelin may closely associated with its alleviation in neuroinflammation.

Chronic morphine selectively impairs cued fear extinction in rats: implications for anxiety disorders associated with opiate use.

Previous studies have shown that opioid transmission plays an important role in learning and memory. However, little is known about the course of opiate-associated learning and memory deficits after cessation of chronic opiate use in a behavioral animal model. In the present study, we examined the effects of chronic morphine on fear extinction, an important preclinical model for behavior therapy of human anxiety disorders. Rats were administrated subcutaneously morphine hydrochloride or saline twice per day for continuous 10 days. Rats received a cued or contextual fear conditioning session 7 days after the last morphine injection. During subsequent days, rats received four cued or contextual extinction sessions (one session per day). Percent freezing was assessed during all phases of training. Chronic morphine did not affect the acquisition of cued fear response or the initial encoding of extinction memory within each session, but produced an impairment in the between-session extinction. However, the same morphine treatment schedule did not affect the acquisition or extinction of contextual fear response. These results suggest that the effects of chronic morphine on memory for fear extinction are complex. Chronic morphine selectively impairs extinction of cued fear response. This deficit in fear extinction may be one of those critical components that contribute to the high prevalence of anxiety disorders in opiate addicts.