Neuropharmacology最新文献

{"title":"Early postnatal reelin treatment suppresses epileptic spasms in a rat model of cortical malformation","authors":"Minyoung Lee ,&nbsp;Eun-Jin Kim ,&nbsp;Mi-Sun Yum","doi":"10.1016/j.neuropharm.2025.110637","DOIUrl":"10.1016/j.neuropharm.2025.110637","url":null,"abstract":"<div><div>Malformation of cortical development (MCD) is a major cause of intractable epilepsy and developmental delay in childhood. Reelin, an extracellular matrix glycoprotein, regulates neuronal migration and interneuron development. Therefore, we investigated the therapeutic potential of early postnatal reelin treatment in a rat model of MCD induced by prenatal methyazoxymethanol acetate (MAM) exposure at embryonic day 15. The neonatal rats received either recombinant mouse reelin (10 or 2.5 μg/kg) or vehicle once every 2 days from postnatal day (P) 2 to P14. On P15, N-methyl-D-aspartic acid (NMDA)-induced spasms were evaluated. The 2.5 μg/kg reelin group showed a significant reduction in the number of NMDA-induced spasms compared with the vehicle group (<em>p</em> = 0.043). Further analyses in the 2.5 μg/kg group revealed increase in the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 2 (AMPAR2) and calcium/calmodulin-stimulated protein kinase II (CaMKII), and decreased levels of postsynaptic density protein 95 (PSD95), AMPAR3, and NMDA receptor 1 (NMDAR1) (<em>p</em> &lt; 0.05). Importantly, a marked increase in cortical interneuron expression was observed, suggesting enhanced inhibitory signaling as a key mechanism for the antispasmodic effect. In addition, magnetic resonance imaging showed no significant changes in cortical metabolites, and Golgi staining showed that dendritic arborization remained unchanged. Behavioral assessments revealed no adverse effects associated with reelin administration. In conclusion, early postnatal reelin treatment effectively suppressed spasm susceptibility in MCD rats, likely through increased interneuron expression and selective modulation of synaptic protein levels. These findings support further investigation of reelin as a potential therapeutic strategy for epilepsy associated with MCD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110637"},"PeriodicalIF":4.6,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential effects of central dopamine D2 receptor activation on the dynamic changes of maternal behavior throughout the postpartum period","authors":"Yue Teng ,&nbsp;Ning Ma ,&nbsp;Junqi Wang ,&nbsp;Xinxiu Xiong ,&nbsp;Rong Zhao ,&nbsp;Yu Yang ,&nbsp;Ming Li ,&nbsp;Jun Gao","doi":"10.1016/j.neuropharm.2025.110639","DOIUrl":"10.1016/j.neuropharm.2025.110639","url":null,"abstract":"<div><div>Maternal behavior during the postpartum period is mediated by various neural mechanisms. While dopamine D₂ receptor activation is known to affect maternal behavior in early postpartum, its role in the late postpartum period remains unclear. This study explores the neural mechanisms governing maternal behavior across the early and late postpartum periods by activating D₂ receptors in different maternal brain regions: the ventral tegmental area (VTA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). In the early (postpartum day [PPD] 4–5) and late (PPD 13–14) postpartum period, a dopamine D₂ receptor agonist was microinjected into these regions in lactating rats. Home cage maternal behavior and pup vs. adult male preference were assessed at 10 and 60 min post-injection. In the VTA, D₂ receptor activation reduced pup retrieval and increased latency in the early postpartum, with no significant effects in the late postpartum or on pup preference. In the NAc, D₂ receptor activation increased retrieval latency and reduced pup crouching, licking, and pup preference in the late postpartum, with no significant effects in the early postpartum. In the mPFC, D₂ receptor activation reduced maternal behavior in both periods but increased pup and male exploration during the early postpartum. These findings suggest region- and time-specific roles of D₂ receptors in maternal regulation. In the VTA and NAc, D₂ activation appears to impair maternal behavior by modulating maternal motivation, particularly in a stage-dependent manner. In the mPFC, D₂ receptors may regulate maternal behavior through both motivational and executive control mechanisms depending on postpartum timing.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110639"},"PeriodicalIF":4.6,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type I interferon signaling promotes kainic acid-induced seizures through mTOR activation","authors":"Jeong-Hwa Ma ,&nbsp;Jun-Cheol Eo ,&nbsp;Changjun Lee ,&nbsp;Jihye Choi ,&nbsp;Inhwa Hwang ,&nbsp;Yun-Jeong Yang ,&nbsp;Sung Jae Shin ,&nbsp;Chul Hoon Kim ,&nbsp;Je-Wook Yu","doi":"10.1016/j.neuropharm.2025.110634","DOIUrl":"10.1016/j.neuropharm.2025.110634","url":null,"abstract":"<div><div>Epilepsy is a chronic neurological disorder characterized by recurrent seizures, yet the role of type I interferon (IFN) signaling in seizure pathogenesis remains elusive. In this study, we show that deficiency of type I IFN signaling reduces seizure severity in a kainic acid-induced mouse model. <em>Ifnar1</em>^{<em>−/−</em>} mice exhibited significantly lower seizure scores at multiple time points (e.g., U = 88.5, <em>p</em> = 0.0078 at 110 min), along with decreased neuronal excitability and microglial activation in these mice in response to kainic acid stimulation. Conversely, intracerebroventricular injection of IFN-β exacerbated kainic acid-induced seizure severity. <em>In vitro</em> calcium imaging demonstrated that IFN-β treatment enhanced neuronal excitability, although no significant difference in basal neuronal excitability were observed between wild-type and <em>Ifnar1</em>^−/− neurons. Additionally, <em>Ifnar1</em>^−/− mice showed reduced activation of the mammalian target of rapamycin (mTOR) pathway in the brain following kainic acid administration-a pathway known to contribute to epileptogenesis. Consistent with this finding, IFN-β treatment increased mTOR activation, as indicated by S6 phosphorylation in <em>in vitro</em> mixed glial cultures. Taken together, these findings highlight a critical role of type I IFN signaling in seizure progression, potentially via mTOR modulation, and suggest that targeting type I IFNs may offer a promising therapeutic strategy for epilepsy.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110634"},"PeriodicalIF":4.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monotropein alleviates sepsis-associated encephalopathy by targeting matrix metalloproteinase-9","authors":"Yue Xin ,&nbsp;Tianyue Guan ,&nbsp;Guanglu Wang ,&nbsp;Yannan Xiang ,&nbsp;Mengxin Li ,&nbsp;Yikun Zhao ,&nbsp;Panpan Zhao","doi":"10.1016/j.neuropharm.2025.110636","DOIUrl":"10.1016/j.neuropharm.2025.110636","url":null,"abstract":"<div><div>Sepsis is a severe systemic infection that leads to multiple organ dysfunction and high mortality, making it one of the primary causes of death in ICU patients. Sepsis also induces septic encephalopathy (SAE), resulting in acute and long-term cognitive impairments. Research indicates that inhibiting BBB damage, anti-inflammatory, and antioxidant responses are critical therapeutic directions for SAE. Monotropein (Mon), the main active component of the traditional Chinese medicine Epimedium, possesses various pharmacological effects, including antioxidant properties. This study aims to explore the protective effects and potential targets of Mon in SAE. Firstly, the GEO database was utilized to screen for highly expressed genes, identifying matrix metalloproteinase-9 (MMP9) as a target. Drug target reverse screening using Schrodinger software confirmed MMP9 as a potential therapeutic target for Mon. Subsequently, <em>in vitro</em> experiments using an LPS-stimulated BV-2 and HUVECs co-culture model examined the interaction between Mon and MMP9. A CLP-induced mouse model was employed to investigate Mon's role in SAE. Results indicate that MMP9 is highly expressed in SAE and promotes its progression. Mon targets MMP9, enhancing its protein stability and exerting anti-inflammatory, improved vascular permeability, and barrier protective effects. Mon alleviates brain tissue damage, BBB disruption, and synaptic loss induced by CLP, increases antioxidant enzyme activity to eliminate ROS, and suppresses sepsis-induced oxidative stress, thereby mitigating CLP-induced cognitive impairment in mice. In conclusion, Mon targets MMP9, exerting anti-inflammatory, antioxidant, and barrier protective effects, alleviating SAE. Mon may serve as a potential natural therapeutic agent for treating sepsis-induced brain dysfunction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110636"},"PeriodicalIF":4.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabidiol prevents social avoidance, potentiation of cocaine reward and gene expression alterations induced by exposure to intermittent social defeat in mice","authors":"Maria Ángeles Martínez-Caballero ,&nbsp;Daniela Navarro ,&nbsp;Claudia Calpe-López ,&nbsp;Abraham B. Torregrosa ,&nbsp;Maria Pilar García-Pardo ,&nbsp;Jorge Manzanares ,&nbsp;Maria Asunción Aguilar","doi":"10.1016/j.neuropharm.2025.110630","DOIUrl":"10.1016/j.neuropharm.2025.110630","url":null,"abstract":"<div><div>Exposure to intermittent social defeat (ISD), a model of social stress, increased anxiety- and depression-like behaviors and enhanced sensitivity of mice to the rewarding effects of cocaine. In this study, we evaluated the role of cannabidiol on these behavioral effects of ISD and ISD-induced alterations in targets of the serotonin, endocannabinoid and hypothalamus-pituitary-adrenal (HPA) systems. Male mice were treated with cannabidiol (30 or 60 mg/kg) and exposed to four episodes of social defeat on PND 47, 50, 53 and 56. Control mice were not exposed to stress. In experiment 1, on PND 57–58, mice were tested in several behavioral tests and, three weeks later, underwent a cocaine-induced conditioned place preference. In experiment 2, the gene expression of the serotonin transporter in the dorsal raphe, corticotrophin-releasing factor in the paraventricular nucleus, proopiomelanocortin in the arcuate nucleus and the glucocorticoid and cannabinoid receptors in the hippocampus were evaluated after the last episode of defeat. CBD reversed the social interaction deficit and the potentiation of cocaine preference, but not anxiety-like effects induced by ISD. In addition, except for the glucocorticoid receptor, ISD reduced gene expression, and this effect was reversed by cannabidiol. Our results indicated the involvement of serotonin, HPA and endocannabinoid systems in the effects of social stress. They showed that CBD is a promising therapeutic agent to prevent social avoidance, enhanced vulnerability to cocaine and gene expression alterations in stress-exposed individuals.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110630"},"PeriodicalIF":4.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144830183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perinatal fluoxetine exposure increases male rat sexual behavior","authors":"Ane K. Baann ,&nbsp;Danielle J. Houwing ,&nbsp;Jocelien D.A. Olivier ,&nbsp;Roy Heijkoop ,&nbsp;Eelke M.S. Snoeren","doi":"10.1016/j.neuropharm.2025.110635","DOIUrl":"10.1016/j.neuropharm.2025.110635","url":null,"abstract":"<div><div>Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women due to their efficacy and safety profile, leading to potential exposure of the developing fetus and infant. Serotonin, which acts as a neurotransmitter in adults and is crucial for regulating male sexual behavior, also serves as a neurotrophic factor during early brain development. Yet, the long-term consequences of perinatal SSRI exposure on adult sexual functioning remain poorly understood. This study investigates the long-term effects of perinatal SSRI exposure on the sexual behavior of adult male rats in a seminatural environment. During pregnancy and lactating, mother rats were administered either fluoxetine (FLX, 10 mg/kg) or a control solution (CTR, 1 % Methylcellulose) daily via oral gavage. Upon reaching adulthood, male offspring were assessed for sexual performance in a semi-natural setting, where they lived in mixed-sex groups for eight days. Comprehensive observations of sexual, social, and conflict behaviors were scoring from the first to the last copulatory behavior during the period in which female rats were sexually receptive. Our findings reveal that perinatal FLX exposure significantly increases sexual behavior in adult male rats, as evidenced by a higher total number of copulatory behaviors. This suggests that elevated serotonin levels during early development have enduring consequences for male rat sexual behavior in adulthood, potentially enhancing reproductive strategies and success in naturalistic environments.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110635"},"PeriodicalIF":4.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent isolation disrupts medial amygdala and ventral tegmental area maturation and sex-specifically dysregulates transcriptional responses to cocaine and stress","authors":"Mason D. Andrus ,&nbsp;Theresa Vu ,&nbsp;Barbara Juarez ,&nbsp;Deena M. Walker","doi":"10.1016/j.neuropharm.2025.110629","DOIUrl":"10.1016/j.neuropharm.2025.110629","url":null,"abstract":"<div><div>Adolescence is a sensitive developmental period marked by immense social and neural changes during which stressful experiences are associated with susceptibility to neuropsychiatric disorders. The medial amygdala (meA) is especially sensitive to the persistent transcriptional effects of adolescent social isolation. Although critical for social reward, the meA is generally considered to be outside the canonical reward circuitry; however, tracing studies reveal extensive connectivity of the meA with reward circuitry. Here, we show that cocaine-responsive transcriptional concordance is disrupted between the meA and ventral tegmental area (VTA) but not other regions of the mesocorticolimbic reward circuitry by adolescent isolation. This loss of concordance is driven by sex-specific differences in stimulus- and cocaine-responsive gene transcription within and between meA–VTA. We use retrograde tracing techniques to show that these effects are not due to differences in meA–VTA connectivity, nor are they due to differences in dopamine neuronal firing rate in the VTA. Finally, we find that adolescent isolation induced sex-specific disruption of maturational profiles of glutamatergic signaling genes in the meA and VTA. In the meA, isolation increased gene expression of glutamatergic markers <em>Camk2b</em> and <em>Slc17a7</em> in females, but decreased expression of <em>Camk2a</em> and <em>Camk2b</em> in males. In the VTA, isolation increases expression of NMDA receptor subunits <em>Grin1</em> and <em>Grin2b</em> in females, while reducing <em>Grin1</em> and increasing dopamine receptor <em>Drd2</em> expression in males. These findings establish an integral role of a meA–VTA circuit in the etiology and expression of features of adolescent-onset neuropsychiatric disruptions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110629"},"PeriodicalIF":4.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The glutaminase inhibitor JHU-083 mitigates cognitive dysfunction in a mouse model of post-traumatic stress disorder","authors":"Zhihui Liu ,&nbsp;Li Huang ,&nbsp;Weichen Dong ,&nbsp;Linying Yuan ,&nbsp;Yuanfei Luo ,&nbsp;Ying Zhao ,&nbsp;Lulu Xiao ,&nbsp;Jia Wang ,&nbsp;Rui Liu ,&nbsp;Yulong Cai ,&nbsp;Wusheng Zhu","doi":"10.1016/j.neuropharm.2025.110631","DOIUrl":"10.1016/j.neuropharm.2025.110631","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is characterized by symptoms including re-experiencing, avoidance, hyperarousal, and negative alterations in cognition and mood as defined by DSM-5. It is frequently accompanied by comorbid conditions such as anxiety, depression, and cognitive impairments, which are primarily attributed to abnormal hippocampal neuronal damage and impaired synaptic plasticity. Glutaminase (GLS), a key enzyme in the synthesis of glutamate within the brain, plays a role in regulating neurodevelopment and synaptic excitability. However, the impact of GLS inhibition on neuronal repair and synaptic plasticity in PTSD models remains unclear. We established a traumatic stress model using the single prolonged stress combined with foot shock (SPS&amp;S) method, which simulates aspects of trauma-related behaviors, such as anxiety-like, depressive-like, and cognitive impairments. We evaluated the efficacy of the GLS inhibitor JHU-083 in PTSD model mice by assessing indicators related to anxiety and depression levels, cognitive function, neuronal damage, and synaptic plasticity. Our results show that JHU-083 treatment alleviates behavioral abnormalities in PTSD model mice. The therapeutic effect of JHU-083 is associated with improved hippocampal neuronal repair and enhanced synaptic plasticity. Furthermore, JHU-083 may enhance neurocognitive function and ameliorate hippocampal synaptic deficits in PTSD model mice through the PI3K signaling pathway. These findings suggest that the GLS inhibitor JHU-083 can improve anxiety and cognitive dysfunction in mice exhibiting PTSD-like behaviors, likely by enhancing neuronal repair and synaptic plasticity in the hippocampus via modulation of the PI3K signaling pathway.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110631"},"PeriodicalIF":4.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nexilin regulates cell surface expression of extrasynaptic GABAA receptors by binding to actin","authors":"Damian P. Bright ,&nbsp;Clemens Schulte ,&nbsp;Elise F. Halff ,&nbsp;Michael J. Lumb ,&nbsp;Josef T. Kittler ,&nbsp;Hans M. Maric ,&nbsp;Trevor G. Smart","doi":"10.1016/j.neuropharm.2025.110633","DOIUrl":"10.1016/j.neuropharm.2025.110633","url":null,"abstract":"<div><div>Controlling cell-surface expression of GABA_A receptors is vital for homeostatic maintenance of inhibitory transmission within the brain. Here, we describe a novel interaction between the actin-binding protein nexilin and extrasynaptic γ2 subunit-containing GABA_A receptors. Pulldowns, array-based mapping, and deep-mutational scanning indicate that nexilin binding depends on a distinct motif conserved within the C-terminal ends of GABA_A γ-subunit intracellular loops. Manipulation of nexilin levels in hippocampal neurons leads to correlated changes in GABA-mediated currents and GABA_A receptor surface expression. This regulation is critically dependent upon nexilin binding to actin, since deletion of the actin-binding domain ablates the effects on GABA_A receptor expression. Nexilin upregulation leads to an increase in synaptic GABA_A receptor numbers, whilst down-regulation has no effect on synaptic currents, suggesting that nexilin is particularly important only for extrasynaptic γ2-GABA_A receptors. However, altering nexilin expression also impacts upon inhibitory synaptic plasticity, possibly reflecting the altered availability of receptors anchored in the extrasynaptic membrane. Nexilin control of extrasynaptic γ2-GABA_A receptor expression levels represents a new regulatory mechanism for both tonic and phasic inhibition.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110633"},"PeriodicalIF":4.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salt-inducible kinase 1 and CREB-regulated transcription co-activator 1 in the paraventricular nucleus participate in the antidepressant-like mechanism of (2R, 6R)-hydroxynorketamine and (2S, 6S)-hydroxynorketamine in mice","authors":"Jun-Jie Qian ,&nbsp;Feng Zhang ,&nbsp;Wei-Jia Chen ,&nbsp;Bao-Lun Zhu ,&nbsp;Fei-Yang Jin ,&nbsp;Jia-Yi Shen ,&nbsp;Bo Jiang ,&nbsp;Hua Fan","doi":"10.1016/j.neuropharm.2025.110632","DOIUrl":"10.1016/j.neuropharm.2025.110632","url":null,"abstract":"<div><h3>Background</h3><div>Previous studies have demonstrated that ketamine's metabolic conversion to (2<em>S</em>, 6<em>S</em>; 2<em>R</em>, 6<em>R</em>)-HNK is indispensable for its fast-onset and long-lasting antidepressant-like actions, and moreover, both (2<em>R</em>, 6<em>R</em>)-HNK and (2<em>S</em>, 6<em>S</em>)-HNK exert N-methyl-D-aspartate receptor (NMDAR)-independent antidepressant-like activities. Up to date, many pharmacological targets other than NMDAR have been reported for (2<em>R</em>, 6<em>R</em>)-HNK and (2<em>S</em>, 6<em>S</em>)-HNK. We have previously found that salt-inducible kinase 1 (SIK1) and cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) participate in depression neurobiology by regulating the hypothalamic-pituitary-adrenal (HPA) axis, and here, we assume that (2<em>R</em>, 6<em>R</em>)-HNK and (2<em>S</em>, 6<em>S</em>)-HNK may also produce effects on the two molecules.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice, chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), behavioral tests, enzyme linked immunosorbent assay (ELISA), western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene knockdown were adopted.</div></div><div><h3>Results</h3><div>Administration of (2<em>R</em>, 6<em>R</em>)-HNK/(2<em>S</em>, 6<em>S</em>)-HNK fully reversed both CUMS-induced and CSDS-induced depressive-like behaviors, HPA hyperactivity, and dysfunction in the SIK1-CRTC1 system in the PVN of mice. AAV-mediated genetic knock-down of SIK1 in PVN neurons significantly abolished the reversal effects of (2<em>R</em>, 6<em>R</em>)-HNK and (2<em>S</em>, 6<em>S</em>)-HNK against CUMS and CSDS.</div></div><div><h3>Conclusions</h3><div>SIK1 and CRTC1 in PVN neurons participate in the antidepressant-like mechanism of (2<em>R</em>, 6<em>R</em>)-HNK and (2<em>S</em>, 6<em>S</em>)-HNK, extending the knowledge of their pharmacological targets.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"279 ","pages":"Article 110632"},"PeriodicalIF":4.6,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}