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Zhu W.-L.,Peking University | Wang S.-J.,Peking University | Liu M.-M.,Peking University | Shi H.-S.,Peking University | And 5 more authors.
Journal of Psychiatry and Neuroscience | Year: 2013

Background: Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA. Methods: We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3β (p-GSK3β) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus. Results: Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3β, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3β by LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential. Limitations: It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3β and mTOR signalling, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study. Conclusion: Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3β and mTOR signalling function in the mPFC. © 2013 Canadian Medical Association.

Shi H.-S.,Peking University | Shi H.-S.,Hebei Medical University | Zhu W.-L.,Peking University | Liu J.-F.,Peking University | And 8 more authors.
Neuropsychopharmacology | Year: 2012

Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants. © 2012 American College of Neuropsychopharmacology.

Wang Y.-Y.,Peking University | Qin J.,Peking University | Han Y.,Peking University | Cai J.,Peking University | And 2 more authors.
Brain Research | Year: 2011

Febrile seizures (FS), or fever-induced seizures, are the most common form of seizures during childhood. Although simple FS are usually considered benign, prolonged or recurrent FS are proposed to increase the risk for developing subsequent temporal lobe epilepsy (TLE) in adults. The pathophysiology of FS is still largely unknown. In this study, by using whole-cell patch-clamp recording techniques, we demonstrated that hyperthermia (39-40 °C) induced a "febrile seizure-like event" expressed as spontaneous, recurrent, epileptiform discharges (SREDs) followed by a series of sustained depolarizations (SDs) in cultured rat cortical neurons (7-14 DIV). The SREDs were characterized by abruptly developing, paroxysmal depolarizing shifts (PDS) of membrane potential with high-frequency spike firing characteristic of electrographic seizures. Furthermore, we also found that hyperthermia induced persistent neuronal hyperexcitability as assessed by their intrinsic electrogenic characteristics which include: 1) depolarized resting potential (RP); 2) decreased input resistance (R in); 3) a marked decrease in amplitude, duration and afterhyperpolarization (AHP) of spontaneous action potentials; 4) a prominent reduction in action potential (AP) current threshold (I th) and potential threshold (TP); and 5) a dramatic shortened duration, decreased inter-spike intervals (ISI), and increased firing frequency of evoked action potentials. Additionally, our present study also revealed that baclofen (100 μM), a specific GABA B receptor agonist, significantly repressed the hyperthermia-induced neuronal hyperexcitability and epileptiform discharges in cultured cortical neurons. The results suggest that hyperthermia may induce epileptiform activities in cultured cortical neurons by suppression of the GABA B receptor-mediated inhibition, in turn leading to the development of persistent neuronal hyperexcitability when the cells suffered from heating insult. This study provides a novel cellular model for studying the pathogenetic mechanisms of febrile seizures in vitro. © 2011 Elsevier B.V.

Yi M.,Peking University | Zhang H.,Peking University | Lao L.,University of Maryland, Baltimore | Xing G.-G.,Peking University | And 2 more authors.
Molecular Pain | Year: 2011

Acupuncture and electro-acupuncture (EA) are now widely used to treat disorders like pain. We and others have shown previously that current frequency, intensity and treatment duration all significantly influence the anti-nociceptive effects of EA. There is evidence that stimulating sites also affect the antinociception, with EA applied ipsilaterally to the pain site being more effective under some pain states but contralateral EA under others. It was recently reported that local adenosine A1 receptors were responsible for ipsilateral acupuncture, but what mechanisms specifically mediate the anti-nociceptive effects of contralateral acupuncture or EA remains unclear. In the present study, we applied 100 Hz EA on the ipsi- or contra-lateral side of rats with inflammatory pain induced by intra-plantar injection of formalin, and reported distinct anti-nociceptive effects and mechanisms between them. Both ipsi- and contra-lateral EA reduced the paw lifting time in the second phase of the formalin test and attenuated formalin-induced conditioned place aversion. Contralateral EA had an additional effect of reducing paw licking time, suggesting a supraspinal mechanism. Lesions of rostral anterior cingulate cortex (ACC) completely abolished the anti-nociceptive effects of contra- but not ipsi-lateral EA. These findings were not lateralized effects, since injection of formalin into the left or right hind paws produced similar results. Overall, these results demonstrated distinct anti-nociceptive effects and mechanisms between different stimulating sides and implied the necessity of finding the best stimulating protocols for different pain states. © 2011 Yi et al; licensee BioMed Central Ltd.

Cai J.,Peking University | Fang D.,Peking University | Liu X.-D.,Peking University | Li S.,Peking University | And 3 more authors.
Oncology Reports | Year: 2015

Primary and metastatic cancers that affect bones are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. In the present study, we investigated whether inhibition of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the development of bone cancer pain via sensitization of dorsal horn wide dynamic range (WDR) neurons. Using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumor cells, we observed a significant increase in C-fiber responses of dorsal horn WDR neurons in the MRMT-1 injected rats, indicating sensitization of spinal WDR neurons in bone cancer rats. Furthermore, we discovered that blockade of KCNQ/M channels in the spinal cord by local administration of XE-991, a specific KCNQ/M channel blocker, caused a robust increase in excitability of dorsal horn WDR neurons, while, producing obvious pain hypersensitivity in normal rats. On the contrary, activation of spinal KCNQ/M channels by retigabine, a selective KCNQ/M channel opener, not only inhibited the bone cancer-induced hyperexcitability of dorsal horn WDR neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in the bone cancer rats, while all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. All things considered, these results suggest that suppression of KCNQ/M channels in the spinal cord likely contributes to the development of bone cancer pain via sensitization of dorsal horn WDR neurons in rats following tumor cell inoculation.

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