Acupuncture alleviates inflammatory pain by activating CXCL1/CXCR2 signaling in the primary somatosensory cortex in adjuvant induced arthritis rats. / S1脑区CXCL1/CXCR2å‚ä¸Žé’ˆåˆºæ”¹å–„ä½å‰‚æ€§å ³èŠ‚ç‚Žå¤§é¼ ç‚Žæ€§ç—›çš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To observe whether acupuncture up-regulates chemokine CXC ligand 1 (CXCL1) in the brain to play an analgesic role through CXCL1/chemokine CXC receptor 2 (CXCR2) signaling in adjuvant induced arthritis (AIA) rats, so as to reveal its neuro-immunological mechanism underlying improvement of AIA. METHODS: BALB/c mice with relatively stable thermal pain reaction were subjected to planta injection of complete Freund adjuvant (CFA) for establishing AIA model, followed by dividing the AIA mice into simple AF750 (fluorochrome) and AF750+CXCL1 groups (n=2 in each group). AF750 labeled CXCL1 recombinant protein was then injected into the mouse's tail vein to induce elevation of CXCL1 level in blood for simulating the effect of acupuncture stimulation which has been demonstrated by our past study. In vivo small animal imaging technology was used to observe the AF750 and AF750+CXCL1-labelled target regions. After thermal pain screening, the Wistar rats with stable pain reaction were subjected to AIA modeling by injecting CFA into the rat's right planta, then were randomized into model and manual acupuncture groups (n=12 in each group). Other 12 rats that received planta injection of saline were used as the control group. Manual acupuncture (uniform reinforcing and reducing manipulations) was applied to bilateral "Zusanli" (ST36) for 4×2 min, with an interval of 5 min between every 2 min, once daily for 7 days. The thermal pain threshold was assessed by detecting the paw withdrawal latency (PWL) using a thermal pain detector. The contents of CXCL1 in the primary somatosensory cortex (S1), medial prefrontal cortex, nucleus accumbens, amygdala, periaqueductal gray and rostroventromedial medulla regions were assayed by using ELISA, and the expression levels of CXCL1, CXCR2 and mu-opioid receptor (MOR) mRNA in the S1 region were detected using real time-quantitative polymerase chain reaction. The immune-fluorescence positive cellular rate of CXCL1 and CXCR2 in S1 region was observed after immunofluorescence stain. The immunofluorescence double-stain of CXCR2 and astrocyte marker glial fibrillary acidic protein (GFAP) or neuron marker NeuN or MOR was used to determine whether there is a co-expression between them. RESULTS: In AIA mice, results of in vivo experiments showed no obvious enrichment signal of AF750 or AF750+CXCL1 in any organ of the body, while in vitro experiments showed that there was a stronger fluorescence signal of CXCL1 recombinant protein in the brain. In rats, compared with the control group, the PWL from day 0 to day 7 was significantly decreased (P<0.01) and the expression of CXCR2 mRNA in the S1 region significantly increased in the model group (P<0.05), while in comparison with the model group, the PWL from day 2 to day 7, CXCL1 content, CXCR2 mRNA expression and CXCR2 content, and MOR mRNA expression in the S1 region were significantly increased in the manual acupuncture group (P<0.05, P<0.01). Immunofluorescence stain showed that CXCR2 co-stained with NeuN and MOR in the S1 region, indicating that CXCR2 exists in neurons and MOR-positive neurons but not in GFAP positive astrocytes. CONCLUSIONS: Acupuncture can increase the content of CXCL1 in S1 region, up-regulate CXCR2 on neurons in the S1 region and improve MOR expression in S1 region of AIA rats, which may contribute to its effect in alleviating inflammatory pain.

Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats.

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-3ß (p-GSK3ß) 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-GSK3ß, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3ß 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 GSK3ß 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 GSK3ß and mTOR signalling function in the mPFC.

Pathological pathway analysis in an experimental rheumatoid arthritis model and the tissue repair effect of acupuncture at ST36.

Rheumatoid arthritis (RA) is an autoimmune disease that generally affects the joints. In the face of inflammation-induced cartilage and bone damage, RA treatment remains insufficient. While research evidence indicates that acupuncture can exert anti-inflammatory and analgesic effects, improve the joint function of RA patients, and delay the disease, data on whether it can promote RA repair are lacking. Findings from the present work demonstrated that both the antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) models can simulate joint swelling of RA. The AIA model was more stable than the CIA model, with a higher incidence of successful arthritis modeling. Moreover, the AIA mice model could simulate the signal molecules and related pathological processes of the autoimmune response in RA, as well as major pathways related to RA and antigen immune response mechanisms. Manual acupuncture (MA) at Zusanli (ST36) significantly improved paw redness and swelling, pain, and inflammatory cell infiltration in the joints in AIA mice. The therapeutic effect of MA on AIA is achieved primarily through the regulation of steroid hormone biosynthesis, cell metabolism, and tissue repair processes. MA at ST36 can increase the gene contents of tissue repair growth factors, including PEG3, GADD45A, GDF5, FGF5, SOX2, and ATP6V1C2 in the inflammatory side joints of AIA mice, as well as the gene expression of the anti-inflammatory cytokine IL-10. In conclusion, acupuncture may alleviate RA in the joints via modulating the tissue healing process.

Increased Cdk5/p35 activity in the dentate gyrus mediates depressive-like behaviour in rats.

Depression is one of the most pervasive and debilitating psychiatric diseases, and the molecular mechanisms underlying the pathophysiology of depression have not been elucidated. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity underlying learning, memory, and neuropsychiatric disorders. However, whether Cdk5 participates in the development of depressive diseases has not been examined. Using the chronic mild stress (CMS) procedure, we examined the effects of Cdk5/p35 activity in the hippocampus on depressive-like behaviour in rats. We found that CMS increased Cdk5 activity in the hippocampus, accompanied by translocation of neuronal-specific activator p35 from the cytosol to the membrane in the dentate gyrus (DG) subregion. Inhibition of Cdk5 in DG but not in the cornu ammonis 1 (CA1) or CA3 hippocampal subregions inhibited the development of depressive-like symptoms. Overexpression of p35 in DG blocked the antidepressant-like effect of venlafaxine in the CMS model. Moreover, the antidepressants venlafaxine and mirtazapine, but not the antipsychotic aripiprazole, reduced Cdk5 activity through the redistribution of p35 from the membrane to the cytosol in DG. Our results showed that the development of depressive-like behaviour is associated with increased Cdk5 activity in the hippocampus and that the Cdk5/p35 complex plays a key role in the regulation of depressive-like behaviour and antidepressant actions.

Green tea polyphenols produce antidepressant-like effects in adult mice.

Recent studies have shown that a higher consumption of green tea leads to a lower prevalence of depressive symptoms in elderly individuals. However, no studies have explored the antidepressant-like effect of green tea in preclinical models of depression. The aim of this study was to investigate the antidepressant-like effects and the possible mechanism of action of green tea in widely used mouse models of depression. Mice were orally administered green tea polyphenols (GTP; 5, 10 and 20mg/kg) for 7days and assessed in the forced swimming test (FST) and tail suspension test (TST) 60min after the last GTP administration. Serum corticosterone and adrenocorticotrophic hormone (ACTH) levels were also determined immediately after the FST. Green tea polyphenols significantly reduced immobility in both the FST and TST but did not alter locomotor activity in the open field test, suggesting that GTP has antidepressant-like effects, and this action did not induce nonspecific motor changes in mice. Green tea polyphenols also reduced serum corticosterone and ACTH levels in mice exposed to the FST. The present study demonstrated that GTP exerts antidepressant-like effects in a mouse behavioral models of depression, and the mechanism may involve inhibition of the hypothalamic-pituitary-adrenal axis.

[Acupoit is the "transducer" in the physiochemical information coupling response of acupuncture].

Acupoint is the initial response site of acupuncture stimulus and also the source link of the effect onset of acupuncture. Acupuncture is a mechanical physical stimulus. How is the mechanical force of acupuncture transduced into neuroelectrical and biochemical signals at acupoint? How does the physiochemical information of acupoint launch acupuncture effect? All of these remain the common and crucial questions in the study of acupuncture effect mechanism. Physical changes are induced in the local tissue of acupoint by needling techniques, such as the deformation and displacement of muscle fibers, which may act on the nerve ending receptors and produce electroneurographic signals. Besides, these changes may activate the mechanosensitive ion channels of the cytomembrane in acupoint site. Through cellular signal transduction, the physical signals may be transformed into chemical ones to trigger the physiochemical coupling response of acupoint microenvironment. Eventually, acupuncture effect is generated via nerves and body fluids. "The mechanical force of acupuncture", through "the physiochemical transduction", promotes the body's perception and transmits acupuncture signals. It suggests that acupoint is the "transducer" in the physiochemical information coupling response of acupuncture.

[Progress of researches on acupuncture-moxibustion treatment of cartilage damage of osteoarthritis].

Cartilage damage is the key pathological mechanism in the progressive development of osteoarthritis(OA). Slowing down cartilage damage and accelerating cartilage repair are strategies for effective treatment of OA. Acupuncture and moxibustion therapies are widely used in relieving symptoms of OA and have a protective effect on cartilage. In this paper, we reviewed the mechanisms of acupuncture and moxibustion underlying relieving cartilage damage from three aspects: 1) promoting chondrocyte homeostasis by inhibiting apoptosis and improving cellular autophagy, 2) regulating extracellular matrix (ECM) metabolism (inhibiting decomposition and promoting synthesis) by suppressing the release of inflammatory factors and the activity of proteolytic enzymes, and 3) improving OA microenvironment by reducing the number of macrophagocyte 1 (M1) and increasing the ratio of M2/M1 in the local inflammatory locus. In addition, most studies on the mechanisms of acupuncture and moxibustion underlying remission of OA focus on the improvement of pathological changes, such as joint histopathology, cartilage morphology, synovial inflammatory reaction and infiltration, subchondral bone remodeling, etc., thus, the exact functions of acupuncture and moxibustion in ameliorating cartilage injury remain unknown. In view of the important role of mitochondrial dysfunction in promoting OA development and cartilage damage and the current use of tissue engineering methods of chondrocytes and mesenchymal stem cells to repair articular cartilage injury, it is highly recommended that future studies should pay more attention to these aspects.

The autonomic nervous system: A potential link to the efficacy of acupuncture.

The autonomic nervous system (ANS) is a diffuse network that regulates physiological systems to maintain body homeostasis by integrating inputs from the internal and external environment, including the sympathetic, parasympathetic, and enteric nervous systems (ENS). Recent evidence suggests that ANS is one of the key neural pathways for acupuncture signal transduction, which has attracted worldwide attention in the acupuncture field. Here, we reviewed the basic and clinical research published in PubMed over the past 20 years on the effects of acupuncture on ANS regulation and homeostasis maintenance. It was found that acupuncture effectively alleviates ANS dysfunction-associated symptoms in its indications, such as migraine, depression, insomnia, functional dyspepsia, functional constipation. Acupuncture stimulation on some specific acupoints activates sensory nerve fibers, the spinal cord, and the brain. Using information integration and efferents from a complex network of autonomic nuclei of the brain, such as the insular cortex (IC), prefrontal cortex, anterior cingulate cortex (ACC), amygdala (AMG), hypothalamus, periaqueductal gray (PAG), nucleus tractus solitarius (NTS), ventrolateral medulla (VLM), nucleus ambiguus (AMB), acupuncture alleviates visceral dysfunction, inflammation via efferent autonomic nerves, and relieves pain and pain affect. The modulating pattern of sympathetic and parasympathetic nerves is associated with acupuncture stimulation on specific acupoints, intervention parameters, and disease models, and the relationships among them require further exploration. In conclusion, ANS is one of the therapeutic targets for acupuncture and mediates acupuncture's actions, which restores homeostasis. A systemic study is needed to determine the rules and mechanisms underlying the effects of acupoint stimulation on corresponding organs mediated by specific central nervous networks and the efferent ANS.

Hippocampal CA3 calcineurin activity participates in depressive-like behavior in rats.

Calcineurin is a serine/threonine protein phosphatase that regulates neurotransmission, neuronal structure and plasticity, and neuronal excitability in mood disorders, including depression. Increasing evidence has suggested that calcineurin is involved in the regulation of depressive-like behavior. However, little is known about the neurobiological mechanisms that underlie the mood-regulating effects of calcineurin. We investigated the potential mechanism by which calcineurin mediates the development of depressive-like behavior and the involvement of calcineurin in the action of antidepressant medication in the chronic mild stress (CMS) model. The results showed that rats exposed to CMS had decreased calcineurin activity, measured by increased phospho-synapsin I S62/67 (pSynapsin) and decreased calcineurin-Aα levels, specifically in the CA3 but not CA1 or dentate gyrus (DG) subfields of the hippocampus. Calcineurin inhibition in the CA3 but not DG by microinfusion of cyclosporine-A (2 µg) induced depressive-like behavior in normal rats and exacerbated depressive-like performance in CMS-treated rats. Additionally, calcineurin inhibition in the CA3 but not DG reversed the antidepressant-like activity of venlafaxine. Calcineurin inhibition in the CA3 also reduced metabotropic glutamate 2/3 receptor (mGluR2/3) expression levels. mGluR2/3 activation by its agonist LY354740 (100 ng) in the CA3 reversed the depressive-like behavior induced by cyclosporine-A administration. Finally, chronic venlafaxine (40 mg/kg) treatment increased calcineurin activity, reflected by decreased pSynapsin and increased calcineurin-Aα protein levels in the CA3 but not CA1 or DG. These findings indicate that CA3 calcineurin signaling probably mediated through mGluR2/3 participates in the development of depression and the behavioral responses to antidepressant treatment.

Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway.

AIM: The dorsal striatum has been proposed to contribute to the formation of drug-seeking behaviors, leading to excessive and compulsive drug usage, such as addiction. The current study aimed to investigate the involvement of extracellular signal-regulated kinase (ERK) pathway in the modification of striatal synaptic plasticity. METHODS: Ethanol was administered to rats in drinking water at concentration of 6% (v/v) for 30 days. Rats were sacrificed on day 10, 20, or 30 during ethanol intake or on withdrawal day 1, 3, or 7 following 30-d ethanol intake. The striata were removed either for electrophysiological recording or for protein immuno-blot analysis. Extracellular recording technique was used to record population spikes (PS) induced by high-frequency stimulation (HFS) in the dorsolateral striatum (DLS). RESULTS: Corticostriatal long-term depression (LTD) was determined to be dependent upon ERK signaling. Chronic ethanol intake (CEI) attenuated ERK phosphorylation and LTD induction, whereas withdrawal for one day (W1D) potentiated ERK phosphorylation and LTD induction. These results showed that the impact of chronic ethanol intake and withdrawal on corticostriatal synaptic plasticity was associated with ethanol's effect on ERK phosphorylation. In particular, pharmacological inhibition of ERK hyper-phosphorylation by U0126 prevented LTD induction in the DLS and attenuated ethanol withdrawal syndrome as well. CONCLUSION: In rat DLS, chronic ethanol intake and withdrawal altered LTD induction via ERK signaling pathway. Ethanol withdrawal syndrome is mediated, at least partly, by ERK hyper-phosphorylation in the DLS.

Exploration of Stratified Evidence Scoring Method of Acupuncture Clinical Practice Guidelines.

Due to its own internal laws of development, Chinese medicine (CM) seems more inclined to empirical medicine in a relatively long historical period. It is considered to be lacking objective and unified clinical practice guidelines (CPGs), and the difficulties in diagnosis and therapeutic effect evaluation comes with it, have restricted its further inheritance, development and international communication. Over the years, our research group has been committed to improving the standardization theory and methodology of CM, also perfecting relative techniques for further application, which are all based on the stratified evidence scoring method. We have already applied this method to 45 issued guidelines, including 5 national guidelines, 3 industrial guidelines, and 37 formulation/revision social organization guidelines. The stratified evidence scoring method has been recognized and used widely. It helps scholars and applicators to study, formulate, publish and popularize the acupuncture therapy clinical practice guidelines better, thus further promotes the development of acupuncture therapy.

Current Tracking on Effectiveness and Mechanisms of Acupuncture Therapy: A Literature Review of High-Quality Studies.

The scientific evidence of acupuncture studies has been improved in recent years, and one of the important manifestations is that more and more acupuncture clinical trials and mechanism researches have been published in the source periodicals of Science Citation Index (SCI). This study summarized the dominant diseases of acupuncture focusing on of acupuncture efficacy and mechanisms, and discussed the existing problems, highlighting the direction of future developments. Most clinical studies were published in journals with journal impact factor (JIF) score of 10 or above, and majority of the basic researches had JIF scores of 5 to 10. The above literature were further divided according to the International Classification of Diseases (ICD). The most concerned diseases in these articles were neurological diseases, musculoskeletal system and connective tissue diseases, tumor and digestive system diseases. The therapeutic effect and mechanism of acupuncture on each kind of disease were summarized. The results showed that the therapeutic effect of acupuncture on nerve injury focused on the anti-oxidation pathway, neuroprotective and anti-inflammatory processes. The antiinflammatory effect also played an important role in the treatment of musculoskeletal diseases. The analgesic effect was underlined in most of these studies. Clinical trials were well carried out on acupuncture curative effect of tumor complications and side effects of chemo-radiotherapy, but the potential mechanisms have not been clarified. Somato-visceral reflex was suggested to be strongly associated with the effects of acupuncture changing the motor activity of the gastrointestinal tract. Functional magnetic resonance imaging studies indicated that non-specific effects play important roles in acupuncture analgesia. Lines of evidence have pointed out that the regulation of neuro-endocrine-immune networks may be a common switch of acupuncture on different nerve system diseases.

Ethanol attenuates the HFS-induced, ERK-mediated LTP in a dose-dependent manner in rat striatum.

BACKGROUND: The striatum has been implicated to play a role in the control of voluntary behavior, and striatal synaptic plasticity is involved in instrumental learning. Ethanol is known to alter synaptic plasticity, in turn altering the behavior of human and animals. However, it remains unclear whether the striatum plays a role in the effects of ethanol on the central nervous system. The objective of this investigation was to study the effects of acute perfusion of ethanol on long-term potentiation (LTP) to elucidate the mechanisms of addictive drugs in the striatum. In addition, we investigated the contribution of intracellular extracellular signal regulated protein kinase (ERK) signaling pathway to corticostriatal LTP induction. METHODS: The stimulation evoked population spikes (PS) were recorded from the dorsomedial striatum (DMS) slices of rat using the extracellular recording technique. The LTP in DMS slices was induced by high-frequency stimulation (HFS). The ERK level of the DMS was assessed with the Western blot technique. RESULTS: U0126, the inhibitor of ERK, eliminated or significantly attenuated the LTP induced by HFS of the PS in the DMS. MK801 and APV, N-methyl-d-aspartic acid receptor (NMDAR) antagonists, inhibited the induction of striatal LTP, and HFS-induced ERK activation decreased in the slices treated with MK801 in the DMS. Clinically relevant concentrations of ethanol (22 to 88 mM) dose-dependently attenuated the HFS-induced striatal LTP and ERK activation in this brain region. CONCLUSIONS: The LTP of the PS in the DMS is, at least partly, mediated by the ERK pathway coupling to NMDARs. Ethanol attenuated the HFS-induced, ERK-mediated LTP in a dose-dependent manner in this brain region. These results indicate that ethanol may change the synaptic plasticity of corticostriatal circuits underlying the learning of goal-directed instrumental actions, which is mediated by an intracellular ERK signaling pathway associated with NMDARs.

Auricle reconstruction with a nickel-titanium shape memory alloy as the framework.

OBJECTIVE: The objective of this study is to explore the biocompatibility and implantability of a nickel-titanium (NiTi) alloy in auricle reconstruction. METHODS AND MATERIALS: Twelve New Zealand rabbits underwent subcutaneous implantation with a NiTi alloy framework shaped like the human auricle under general anesthesia. The implant was inserted after skin expansion. Implant vascularization was evaluated at months 1, 3, 6, 9, and 12 after implantation by histologic analysis. Immunohistochemical methods were used to examine expression of vascular endothelial growth factor in tissue around the implant. The fibrovascular ingrowth rate of implants was determined by bone scanning using (99m)Tc-PYP. The surface of the NiTi alloy implant was examined microscopically with scanning electron microscopy. RESULT: The implant harvested showed only partial vascularization at 1 month and completely vascularized at 3 months. The amount of vascular endothelial growth factor-positive cells was markedly increased at 6 months and reached the highest number at 3 months. The fibrovascular ingrowth rate of implant was assessed by (99m)Tc-PYP bone scan using ratios of (99m)Tc-PYP activity in placement regions versus the contralateral normal region. One rabbit had exposure of the NiTi alloy framework as a result of overlying skin flap necrosis. It was rescued with animal skin without the complete removal of the framework. All the other rabbits tolerated the implant well, and there were no complications. CONCLUSION: The NiTi alloy implant represents an alternative implant for auricular reconstruction.

Region-specific role of Rac in nucleus accumbens core and basolateral amygdala in consolidation and reconsolidation of cocaine-associated cue memory in rats.

RATIONALE AND OBJECTIVES: Drug reinforcement and the reinstatement of drug seeking are associated with the pathological processing of drug-associated cue memories that can be disrupted by manipulating memory consolidation and reconsolidation. Ras-related C3 botulinum toxin substrate (Rac) is involved in memory processing by regulating actin dynamics and neural structure plasticity. The nucleus accumbens (NAc) and amygdala have been implicated in the consolidation and reconsolidation of emotional memories. Therefore, we hypothesized that Rac in the NAc and amygdala plays a role in the consolidation and reconsolidation of cocaine-associated cue memory. METHODS: Conditioned place preference (CPP) and microinjection of Rac inhibitor NSC23766 were used to determine the role of Rac in the NAc and amygdala in the consolidation and reconsolidation of cocaine-associated cue memory in rats. RESULTS: Microinjections of NSC23766 into the NAc core but not shell, basolateral (BLA), or central amygdala (CeA) after each cocaine-conditioning session inhibited the consolidation of cocaine-induced CPP. A microinjection of NSC23766 into the BLA but not CeA, NAc core, or NAc shell immediately after memory reactivation induced by exposure to a previously cocaine-paired context disrupted the reconsolidation of cocaine-induced CPP. The effect of memory disruption on cocaine reconsolidation was specific to reactivated memory, persisted at least 2 weeks, and was not reinstated by a cocaine-priming injection. CONCLUSIONS: Our findings indicate that Rac in the NAc core and BLA are required for the consolidation and reconsolidation of cocaine-associated cue memory, respectively.

PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3.

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.