Neuropharmacology[JOURNAL]
Sun
200 papers
Synbiotics inhibits gut microbiome perturbation-induced prolongation of migraine-like pain by restoring short-chain fatty acid signaling.
Tang Y, Guan L, Li Z … +5 more , Li R, Liu S, Chen B, Jin Y, Tao F
Neuropharmacology · 2026 Jul · PMID 41825506 · Publisher ↗
Migraine is the most common disabling primary headache disorder. However, currently available therapies for migraine pain are still limited. In the present study, we investigated the effects of gut microbiome perturbatio...
Migraine is the most common disabling primary headache disorder. However, currently available therapies for migraine pain are still limited. In the present study, we investigated the effects of gut microbiome perturbation and synbiotics supplementation on migraine-like pain in male mice and explored the underlying mechanism. We observed that the supplementation with synbiotics inhibited Broad-spectrum antibiotics (ABX)-prolonged migraine-like pain. Using 16S rRNA sequencing, we analyzed bacterial composition and abundance in the mouse gut, and we found that the supplementation with synbiotics recovered ABX-reduced Bacteroidota, which produces acetate and propionate in the gut, and such supplementation increased the levels of short-chain fatty acids (SCFAs) in the gut. SCFAs, specifically acetate and propionate, reversed the ABX-caused prolongation of migraine-like pain. We further found that ABX treatment decreased the expression of SCFA receptors in the gut and the supplementation with synbiotics restored the expression of SCFA receptor FFAR2, but not FFAR3, in the gut. Moreover, genetic deletion of FFAR2 in the Ffar2 knockout mice blocked the effect of synbiotics on migraine-like pain. Our results suggest that gut microbiome perturbation contributes to the prolongation of migraine-like pain and synbiotics can inhibit such pain prolongation by recovering disturbed gut microbiome and restoring SCFAs-FFAR2 signaling.
The MAP6-NTS axis in hippocampal CA1 regulates synaptic plasticity and memory.
Jia Y, Lei J, Jiang Y … +4 more , Xue L, Chen T, Wang J, Wei H
Neuropharmacology · 2026 Jun · PMID 41825505 · Publisher ↗
Microtubule-associated Protein 6 (MAP6) is critical for maintaining microtubule stability and synaptic plasticity, and its dysfunction is a key driver of cognitive impairment. However, the molecular mechanisms linking MA...
Microtubule-associated Protein 6 (MAP6) is critical for maintaining microtubule stability and synaptic plasticity, and its dysfunction is a key driver of cognitive impairment. However, the molecular mechanisms linking MAP6 deletion to cognitive deficits remain unclear. Here, we generated a novel Map6 knockout (KO, Map6) mouse model using CRISPR/Cas9-mediated genome editing. Behavioral tests confirmed that Map6 mice exhibited prominent cognitive impairments, primarily in long-term memory and spatial learning. Hippocampal transcriptome profiling identified marked downregulation of neurotensin (Nts) in Map6 mice, which was validated at both mRNA and protein levels. Rescue experiments demonstrated that direct microinjection of neurotensin (NTS) peptide into the hippocampal CA1 subregion significantly improved cognitive deficits in Map6 mice. Electrophysiological recordings further confirmed that NTS restored impaired long-term potentiation (LTP)-a cellular substrate of learning and memory-in the hippocampal CA1 of Map6 mice. Additionally, chemogenetic activation of CA1 NTS-positive (CA1) neurons reversed these synaptic and behavioral phenotypes. Collectively, we delineate a novel pathway wherein MAP6 deletion induces cognitive impairment by suppressing hippocampal NTS expression and secretion, and both exogenous NTS supplementation and NTS signaling activation reverse Map6 deletion-induced synaptic and behavioral deficits. These findings identify NTS as a critical downstream effector of MAP6 in cognitive regulation, offering a potential therapeutic target for cognitive impairment.
Glutamatergic cannabinoid receptor 1 confers neuroprotection against ischemic stroke by suppressing excitotoxicity and anoxic depolarization.
Jiang Y, Tao M, Zhang C … +11 more , Wu J, Xie J, He X, Fan N, Qu W, Wang C, Zhang J, Liu Z, Ren W, Han J, Qiao Y
Neuropharmacology · 2026 Jun · PMID 41825504 · Publisher ↗
Cannabinoid receptor 1 (CB1R) is widely expressed in the brain and implicated in protection against ischemic stroke, yet its cell-type-specific functions remain incompletely understood. To systematically dissect the cont...
Cannabinoid receptor 1 (CB1R) is widely expressed in the brain and implicated in protection against ischemic stroke, yet its cell-type-specific functions remain incompletely understood. To systematically dissect the contributions of excitatory and inhibitory CB1R populations under ischemia, we generated mice with conditional CB1R knockout in glutamatergic (CB1R) or GABAergic (CB1R) neurons, alongside global CB1R deletion, and subjected those mice to permanent focal cerebral ischemia. Ischemic injury was evaluated using infarct volume quantification, histological staining, and neurological behavioral tests. Glutamate dynamics in the ischemic region were monitored using a fluorescent reporter iGluSnFR. The role of Glut-CB1R in synaptic transmission and anoxic depolarization was assessed via electrophysiological recordings under both baseline and ischemic conditions. We found that CB1R mice fully recapitulated the exacerbated ischemic injury and neurological impairment seen in global knockouts, whereas CB1R mice showed no significant phenotype. This functional non-redundancy was attributed to a Glut-CB1R-specific brake on excitotoxicity, as its loss elevated extracellular glutamate after ischemia. Pharmacological inhibition of glutamate N-methyl-D-aspartic acid (NMDA) receptors attenuated the exacerbated neurological deficits in CB1R mice. Electrophysiological recordings revealed enhanced spontaneous excitatory synaptic transmission and accelerated anoxic depolarization in CB1R pyramidal neurons under ischemic conditions. Pharmacological inhibition of endocannabinoid degradation conferred protection against ischemic injury in control mice but failed in CB1R mice, confirming that Glut-CB1R is the obligate mediator of this protection. These findings demonstrate that CB1R-mediated neuroprotection in acute, non-preconditioned ischemia is uniquely dependent on the CB1R expressed in glutamatergic neurons. Glut-CB1R represents a cell-autonomous, and therapeutically actionable target for ischemic stroke.
Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy.
Qiao Y, Huang M, Sun C … +7 more , Du X, Wang Y, Liu Y, Zhang L, Guo Y, Peng L, Peng D
Neuropharmacology · 2026 Jun · PMID 41819485 · Publisher ↗
Defective mitophagy plays key roles in mitochondrial dysfunction, inflammation, and energy deprivation, and this defect can lead to synaptic loss and cognitive decline in Alzheimer's disease (AD). Although pharmacologica...
Defective mitophagy plays key roles in mitochondrial dysfunction, inflammation, and energy deprivation, and this defect can lead to synaptic loss and cognitive decline in Alzheimer's disease (AD). Although pharmacological enhancement of mitophagy has been found to ameliorate cognitive impairment in AD models, therapeutic strategies directly targeting this pathway remain limited. Ajugol, a bioactive iridoid glycoside isolated from Rehmannia glutinosa, has recently been identified as a potential metabolic regulator. In this study, we demonstrated that ajugol markedly alleviates mitochondrial damage and mitophagy impairment in 5 × FAD mice and HT22 cells. Mechanistically, ajugol upregulates BCL2-interacting protein 3 (BNIP3), which recruits LC3 to damaged mitochondria, thereby promoting mitophagosome formation and ultimately contributing to improved cognitive function. Notably, Bnip3 knockdown in hippocampal neurons abolished the beneficial effects of ajugol in 5 × FAD mice, exacerbating mitophagy defects and mitochondrial dysfunction, ultimately impairing cognitive performance. These findings highlight a previously unrecognized mechanism by which ajugol mitigates amyloid pathology, synaptic dysfunction, and cognitive decline in 5 × FAD mice and HT22 cells by enhancing BNIP3-mediated mitophagy, providing a potential therapeutic strategy for AD intervention.
Neuropharmacology of novel synthetic opioids (NSOs): An ever-expanding challenge for public health and safety.
Baumann MH, Glatfelter GC, Vandeputte MM
Neuropharmacology · 2026 Jun · PMID 41802702 · Publisher ↗
Abstract loading — click title to view on PubMed.
Beyond the toad's kiss: Mapping acute 5-MeO-DMT effects on brain connectivity across sex and dose using awake rat neuroimaging.
Cavallaro N, Rai P, Akins D … +6 more , Soltanpour S, Nasseef MT, Ortiz R, Madularu D, Kulkarni PP, Ferris CF
Neuropharmacology · 2026 Jun · PMID 41796937 · Publisher ↗
BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent serotonergic psychedelic with rapid therapeutic potential for depression and anxiety disorders. Despite growing clinical interest, the neurobiological...
BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent serotonergic psychedelic with rapid therapeutic potential for depression and anxiety disorders. Despite growing clinical interest, the neurobiological mechanisms underlying 5-MeO-DMT's acute brain effects remain poorly understood, and potential sex differences in response have not been investigated. We conducted the first functional MRI study of 5-MeO-DMT in awake, drug-naïve rats using BOLD imaging. METHODS: Male (n = 24) and female (n = 24) rats received I.P. injections of vehicle or 5-MeO-DMT (0.01, 0.1, or 1.0 mg/kg) during scanning sessions. BOLD signal changes and resting-state functional connectivity were assessed across 169 brain regions. Negative and positive BOLD volume activations were quantified during acute (1-10 min) and sustained (11-20 min) time windows post-injection, with sex-stratified analyses performed. RESULTS: Females demonstrated markedly enhanced sensitivity to low-dose 5-MeO-DMT (0.1 mg/kg), exhibiting extensive negative BOLD responses that were largely absent in males at the same dose. The 1.0 mg/kg dose induced widespread negative BOLD responses across multiple brain regions in both sexes during the acute window (1-10 min post-injection), with effects substantially diminishing thereafter. Global functional connectivity was significantly reduced across all doses (p < 0.0001), with regional specificity observed in hypothalamic and cerebellar networks. Temporal analysis revealed peak neurobiological effects within the first 10 min, consistent with 5-MeO-DMT's known rapid pharmacokinetics. CONCLUSION: To our knowledge, this is the first fMRI characterization of 5-MeO-DMT in any species, and it reveals a previously unreported sex difference in psychedelic response. The rapid onset and brief duration of peak effects align with 5-MeO-DMT's unique pharmacological profile and clinical reports.
Differential inhibition of the diverse behavioural effects of mu-opioid receptor agonists by progressive receptor depletion.
Brown L, Langreck C, Hough F … +5 more , Nelson M, Briddon SJ, Lane JR, Javitch JA, Canals M
Neuropharmacology · 2026 Jun · PMID 41796936 · Publisher ↗
Mu-opioid receptor (MOR) agonists remain the mainstay treatment for severe acute pain but are limited by adverse effects including respiratory depression and constipation. Compounds with improved therapeutic profiles hav...
Mu-opioid receptor (MOR) agonists remain the mainstay treatment for severe acute pain but are limited by adverse effects including respiratory depression and constipation. Compounds with improved therapeutic profiles have been reported, and reduced intrinsic efficacy has been proposed as one factor contributing to greater separation between antinociceptive and adverse effects. To investigate the contribution of receptor reserve and intrinsic efficacy to the in vivo effects of opioid agonists, we used the pseudo-irreversible MOR antagonist methocinnamox (MCAM) to progressively deplete functional MORs and examined the effects of three MOR agonists-morphine, 7-OH mitragynine, and tianeptine-across multiple behavioural assays in mice. MCAM pretreatment inhibited agonist-induced effects in a dose-dependent manner across all assays. Lower doses of MCAM preferentially attenuated the antinociceptive, forced swim, and gastrointestinal effects of the lower-efficacy agonist 7-OH mitragynine, consistent with increased sensitivity of these behaviours to receptor depletion. In contrast, locomotor activation and respiratory depression induced by all three agonists were inhibited by similar MCAM doses, indicating comparable susceptibility to receptor depletion despite differences in intrinsic efficacy. Together, these findings suggest that differences in functional receptor reserve contribute to some, but not all, MOR-mediated behavioural outcomes. While reduced intrinsic efficacy and receptor reserve can partially explain separation between antinociception and certain adverse effects, additional ligand-dependent factors likely influence the expression of specific opioid-induced behaviours in vivo.
Dose- and sex-related effects of the MAGL inhibitor MCH11 on binge-like ethanol consumption in mice.
Torregrosa AB, García-Gutiérrez MS, Manzanares J
Neuropharmacology · 2026 Jun · PMID 41794284 · Publisher ↗
The effects of MCH11, a novel monoacylglycerol lipase inhibitor, were evaluated on binge-like ethanol consumption using the drinking-in-the-dark paradigm in male and female C57BL/6J mice. Rodents underwent 4 weeks of bin...
The effects of MCH11, a novel monoacylglycerol lipase inhibitor, were evaluated on binge-like ethanol consumption using the drinking-in-the-dark paradigm in male and female C57BL/6J mice. Rodents underwent 4 weeks of binge drinking, and MCH11 (20 and 40 mg kg, i.p.) was administered acutely (day 4, DID-3) or repeatedly (days 1-4, DID-4). Quantitative PCR assessed tyrosine hydroxylase (Th) in the ventral tegmental area (VTA); dopamine receptor 2 (Drd2) in the prefrontal cortex (PFC) and nucleus accumbens (NAc); and mu-opioid receptor (Oprm1), cannabinoid 1 (Cnr1), and cannabinoid 2 (Cnr2) receptors in the NAc. Across the DID paradigm, females consistently consumed more ethanol than males. Acute MCH11 (40 mg kg, i.p.) significantly reduced ethanol intake in both sexes. Following repeated administration, ethanol consumption decreased in females at both tested doses. In contrast, in males, this effect was observed only at the higher dose, indicating sex-related differences in dose sensitivity under chronic treatment conditions. Ethanol exposure induced sex-specific transcriptional adaptations, including male-predominant increases in Th in the VTA and Cnr1 in the NAc, and opposite regulation of Drd2 in the NAc between sexes. Oprm1 in NAc was upregulated in both, with a greater magnitude in males, whereas Cnr2 in NAc and Drd2 in PFC decreased equally. MCH11 modulated ethanol-associated transcriptional changes in males at 40 mg kg and in females at 20 and 40 mg kg, in parallel with the observed behavioral effects. Together, these findings demonstrate that MCH11 attenuates binge-like ethanol consumption, with dose- and sex-related differences, and highlight its therapeutic potential to modulate binge drinking behavior.
Running exercise attenuates excitatory synaptic loss in the medial prefrontal cortex of CUS rats: Potential modulation of microglial and astrocytic synaptic contacts.
Wu XY, Liu S, Xiao Q … +18 more , Tang J, Luo HF, Ren XY, Jiang L, Liang X, Huang DJ, Zhou CN, Zhou YN, Li J, Zhang L, Chao FL, Du L, Dou XY, Deng YH, Liu XX, Pu XL, Tang Y, Luo YM
Neuropharmacology · 2026 Jun · PMID 41794283 · Publisher ↗
Reduction of excitatory synapses in the medial prefrontal cortex (mPFC) is closely associated with depression and can be mitigated by running exercise. However, precise quantitative studies focusing on subregion-specific...
Reduction of excitatory synapses in the medial prefrontal cortex (mPFC) is closely associated with depression and can be mitigated by running exercise. However, precise quantitative studies focusing on subregion-specific excitatory synaptic changes under depression remain limited, and the potential involvement of microglia and astrocytes in exercise-mediated synaptic protection remains unclear. In this study, Sprague-Dawley (SD) rats were subjected to chronic unpredictable stress (CUS) followed by a 6-week treadmill running program. Behavioral assessments included the sucrose preference test and the elevated plus maze test. Nissl staining, immunogold staining, and stereological methods were employed to evaluate the volume of mPFC subregions and the number of dendritic spines in each subregion. Immunofluorescence combined with three-dimensional confocal imaging was used to evaluate microglial and astrocytic density, morphology, and synaptic contacts. Our results demonstrated that running exercise exerted significant antidepressant effects in CUS rats, as evidenced by improved anhedonia-related behaviors. Concurrently, running exercise increased the volume of the mPFC in CUS model rats, particularly in the anterior cingulate cortex (ACC) subregion, and restored the number of dendritic spines across all mPFC subregions. Additionally, running exercise reversed the CUS-induced alterations in microglial and astrocytic morphology and reduced excitatory synapse contacts on glial cells in a subregion-specific manner in the mPFC. These findings provide novel morphological evidence that running exercise protects excitatory synapses in the mPFC, potentially via modulation of glial-synapse interactions, offering insights into the cellular mechanisms underlying exercise-based antidepressant effects.
A novel rat model harboring two BDNF gene mutations exhibiting autism-like behaviors and cognitive impairments.
Xue Z, Lan J, Zhao Y … +4 more , Yu P, Liu L, Lu B, Yang F
Neuropharmacology · 2026 Jun · PMID 41794282 · Publisher ↗
Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that occurs most frequently in early childhood, affecting approximately 1% of the global population. Currently, the elusive nature of the pathologic...
Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that occurs most frequently in early childhood, affecting approximately 1% of the global population. Currently, the elusive nature of the pathological mechanisms underlying ASD precludes the existence of a definitive, effective treatment approach. In this study, we have successfully generated a novel ASD rat model utilizing CRISPR/Cas9 technology, offering a promising platform for further investigation and potential therapeutic interventions. The model is characterized by two crucial point mutations occurring at key enzyme cleavage sites of brain-derived neurotrophic factor (BDNF), thereby causing disruptions in enzyme cleavage processes. The phenotypes of this rat model faithfully recapitulate the salient deficits frequently encountered in ASD patients, exhibiting impairments in social behavior, cognition, and anxiety, along with neuronal abnormalities with key brain regions, notably the hippocampus (HPC) and medial prefrontal cortex (mPFC). Through preliminary RNA-seq analysis, we found changes in gene expression patterns related to synapses and neuronal excitability in these areas, providing new insights into the pathogenesis of ASD. Furthermore, our utilization of 7,8-dihydroxyflavone (7,8-DHF), a robust enhancer for the upregulation of both BDNF and TrkB mRNA and simultaneously activates the BDNF-TrkB signaling pathway, appears to strengthen the BDNF-TrkB signaling cascade. This intervention modifies firing patterns of neuronal spikes and synaptic transmission, which may contribute to the amelioration of ASD-like social interaction behavior exhibited in BDNF rats. Our research not only deepens our understanding of the pathogenesis of ASD, but also present encouraging avenue for early intervention strategies and treatments.
Cannabidiol reduces the latency for the behavioral effect of escitalopram in chronically stressed male mice: involvement of NAPE-PLD expressed in parvalbumin-positive interneurons and the prefrontal cortex.
Scarante F, Lopes VD, Fusse EJ … +14 more , Vicente MA, de Abreu GHD, Nardini V, Sorgi CA, Lirio PHC, Guo F, Lu HC, Hallak JEC, Crippa JA, Faccioli LH, Sales KU, Guimarães FS, Mackie K, Campos AC
Neuropharmacology · 2026 Jun · PMID 41791701 · Publisher ↗
Antidepressant drugs are the first-line treatment for chronic stress-related psychiatric disorders such as major depressive disorder, anxiety disorders, and post-traumatic stress disorder. However, their delayed-onset of...
Antidepressant drugs are the first-line treatment for chronic stress-related psychiatric disorders such as major depressive disorder, anxiety disorders, and post-traumatic stress disorder. However, their delayed-onset of therapeutic action, side effects, and incomplete clinical efficacy impose challenges for clinicians and patients' adherence to treatment. Cannabidiol (CBD) is a major non-psychotomimetic phytocannabinoid with a wide range of potential clinical applications such as either a standalone drug or as an add-on treatment. In our study, we found that in chronically stressed male mice, CBD (30 mg/kg) rapidly induced behavioral improvement within 7 days, which was quicker than the high dose of escitalopram (ESC, 14 days). Additionally, repeated administration of low and initially ineffective dose of CBD (7.5 mg/kg) potentiated the anti-stress effects of ESC (10 mg/kg) in mice subjected to 10 or 21 days of chronic unpredictable stress (CUS). Furthermore, our results suggested the involvement of N-acyl phosphatidylethanolamine phospholipase (NAPE-PLD) located in the prefrontal cortex (PFC) in the anti-stress effects of the 7-day treatment with ESC + CBD. This combination restored CUS-induced decreased expression of NAPE-PLD in the PFC. The behavioral effects of ESC + CBD were not observed in either constitutive NAPE-PLD knockout (KO) mice or mice with a CRISPR/Cas9-induced deletion of NAPE-PLD in the PFC. ESC + CBD treatment facilitated NAPE-PLD expression in parvalbumin (PV) interneurons in the PFC. As a conclusion, we suggest that CBD might be useful as an add-on therapy to optimize the action of (SSRI-)antidepressants, possibly by restoring the inhibitory/excitatory balance of the PFC via NAPE-PLD-mediated signaling.
Anxiety in male psoriasis mouse model is mediated by the interaction between γδ T cell-derived IL-17A and microglia.
Yang J, Zhang S, Fu C … +5 more , Dai Y, Sun Y, Dou X, Lin Y, Wu Y
Neuropharmacology · 2026 Jun · PMID 41780818 · Publisher ↗
OBJECTIVE: Both clinical and animal studies indicate a high incidence of anxiety in psoriasis, though the underlying mechanisms remain poorly understood. Our previous review suggested that T cells, related cytokines, and...
OBJECTIVE: Both clinical and animal studies indicate a high incidence of anxiety in psoriasis, though the underlying mechanisms remain poorly understood. Our previous review suggested that T cells, related cytokines, and blood-brain barrier (BBB) disruption might serve as potential links between the two conditions. This study aimed to investigate the mechanistic connection. METHODS: Psoriasis was induced in male C57BL/6J mice using imiquimod (IMQ). Anxiety-like behaviors were assessed through the open field test, elevated plus maze test, and light-dark box test. Microglial activation was evaluated by immunofluorescence and flow cytometry. Hippocampal inflammatory cytokine expression was measured by Western blot and qRT-PCR. Inflammatory factors in brain and periphery were flow cytometrically analyzed. BBB integrity was examined using Evans blue injection and tight junction protein expression. To elucidate the roles of microglia, IL-17A, and γδ T cells, each of them was separately depleted in psoriasis mouse models, with Tcrd mice used for verification. RESULTS: IMQ-treated mice exhibited significant anxiety-like behaviors, increased pro-inflammatory (CD86) microglial activation, elevated hippocampal IL-17A (mainly derived from γδ T cells), and impaired BBB integrity characterized by reduced ZO-1 and Occludin expression. Depletion of microglia, IL-17A, or γδ T cells significantly alleviated anxiety-like behaviors in psoriasis mouse models. Following microglial depletion, RORγt expression in brain γδ T cells decreased. Conversely, IL-17A neutralization or modeling on Tcrd mice altered microglial activation patterns. CONCLUSION: Psoriasis mouse models exhibit anxiety-like behaviors accompanied by impaired BBB integrity. These effects are associated with γδ T cell-microglia interactions, in which IL-17A plays a crucial role.
Tetramethylpyrazine mitigates ER-stress-driven ATF4/CHOP apoptosis to protect dopaminergic neurons in cellular and MPTP models of Parkinson's disease.
Zhan S, Wen S, Wu L … +4 more , Zhang X, Liu J, Zhang G, Liu H
Neuropharmacology · 2026 Jun · PMID 41771400 · Publisher ↗
Parkinson's disease (PD) is a prevalent neurodegenerative disorder lacking effective disease-modifying therapies, with neuronal death critically linked to endoplasmic reticulum stress (ERS) and the activation of the acti...
Parkinson's disease (PD) is a prevalent neurodegenerative disorder lacking effective disease-modifying therapies, with neuronal death critically linked to endoplasmic reticulum stress (ERS) and the activation of the activating transcription factor 4/activating transcription factor 3/C/EBP homologous protein (ATF4/ATF3/CHOP) pro-apoptotic pathway. This study investigated whether the alkaloid tetramethylpyrazine (TMP) confers neuroprotection by modulating this pathway. Our approach combined bioinformatics, which suggested ATF4 as a potential regulatory node, with mechanistic experiments in cellular (1-methyl-4-phenylpyridinium [MPP]) and mouse (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]) models of PD. In vitro, TMP protected SH-SY5Y cells from apoptosis by downregulating the ATF4 cascade; moreover, the observation that ATF4 silencing phenocopied and occluded TMP's effects confirms that its therapeutic ceiling is dictated by the ATF4 pathway. This mechanism was further explored in vivo, where TMP improved motor function and rescued dopaminergic neurons. Crucially, these therapeutic benefits were largely negated by co-administering Salubrinal (SAL), an inhibitor of eukaryotic initiation factor 2 alpha (eIF2α) dephosphorylation known to sustain ATF4 activation. These findings support a model where TMP's neuroprotective action is associated with the inhibition of the ERS-induced ATF4/CHOP apoptotic axis, highlighting this pathway as a promising therapeutic target for PD.
Fisetin targets multiple signaling pathways to suppress microglia-mediated neuroinflammation and cognitive decline in Alzheimer's disease.
Dai YT, Chen Q, Ma YD … +9 more , Liu H, Zheng HD, Zhu YY, Gao L, Zhao Q, Bai JL, Fan YC, Yan CR, Shi JM
Neuropharmacology · 2026 Jun · PMID 41771399 · Publisher ↗
Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflamm...
Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflammatory characteristics; however, the exact mechanisms via which it mitigates microglial dysfunction in AD are not fully elucidated. This work employed a combination of in vivo and in vitro approaches, utilizing male APP/PS1 mice and ADDL-stimulated primary microglia. Behavioral tests, immunohistochemistry, molecular profiling, and mitochondrial function assays were conducted. This research combines network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) to offer predictive insights. Fisetin treatment improved cognitive performance in APP/PS1 mice, concurrently reducing amyloid pathology and plaque-associated microglial clustering. In primary microglia, fisetin potently inhibited ADDL-induced pro-inflammatory activation, mitochondrial ROS overproduction, and membrane depolarization. PI3K was identified as a signaling node potentially involved in fisetin-mediated regulation of microglial inflammatory responses. Accordingly, fisetin constrained microglial inflammatory signaling, at least in part through modulation of the PI3K-Akt-NF-κB axis, thereby limiting NF-κB nuclear translocation and pro-inflammatory cytokine release in both the mouse hippocampus and cultured primary microglia. Furthermore, conditioned medium from fisetin-treated microglia alleviated neuronal damage and restored the expression of BDNF and PSD95 in primary neurons. The collective findings, along with experimental studies utilizing the PI3K inhibitor (LY294002), indicate that PI3K may act as a molecular target of fisetin, underscoring its potential therapeutic significance in regulating early inflammatory processes in AD.
Hypocretin receptor 1 blockade early in abstinence reduces future demand for cocaine.
Samels SB, Shaw JK, Alonso IP … +3 more , Black EM, Zhang Y, España RA
Neuropharmacology · 2026 Jun · PMID 41765282 · Publisher ↗
Relapse to cocaine use after periods of abstinence remains a significant challenge for treating cocaine use disorder. While the neurobiological mechanisms underlying relapse are still under investigation, adaptations in...
Relapse to cocaine use after periods of abstinence remains a significant challenge for treating cocaine use disorder. While the neurobiological mechanisms underlying relapse are still under investigation, adaptations in mesolimbic dopamine systems may contribute to cocaine craving and propensity for relapse. Therefore, reversing or preventing these dopamine adaptations may reduce motivation for cocaine and decrease the likelihood of relapse. The hypocretin/orexin system has been shown repeatedly to regulate cocaine-associated behavior and dopamine transmission. For example, our previous studies indicated that the hypocretin receptor 1 antagonist-RTIOX-276-reduced behavioral and dopamine responses to cocaine. Importantly, the effects of RTIOX-276 on dopamine transmission persisted for at least 24 hr, suggesting lasting effects of hypocretin receptor antagonism. Here, we hypothesized that a single RTIOX-276 treatment early in abstinence would reduce motivation for cocaine and prevent alterations in dopamine transmission later in abstinence. Female and male rats were pre-assessed for cocaine consumption and motivation using a within-session threshold schedule before undergoing 7 days of intermittent access to cocaine. After intermittent access self-administration, rats were treated with RTIOX-276 on the first day of a 7-day abstinence period, after which they were reassessed for cocaine consumption and motivation or examined for dopamine transmission using fast-scan cyclic voltammetry in nucleus accumbens core slices. We found that a single treatment with RTIOX-276 on the first day of abstinence reduced motivation for cocaine and prevented aberrant dopamine uptake observed following intermittent access to cocaine. These findings suggest that hypocretin receptor 1 may be a viable target for reducing motivation for cocaine through alterations in dopamine transmission in the nucleus accumbens.
Dentate gyrus microglial dynamics contributes to high-fat diet-induced depression-like behaviors in mice.
Zhu T, Ye M, Huang C … +6 more , Jiang Y, Gu Y, Cao Z, Xu F, Su J, Yang R
Neuropharmacology · 2026 Feb · PMID 41765281 · Publisher ↗
High-fat diet (HFD) consumption is a harmful habit worldwide that can lead to various problems, including an increased risk of depression. However, the mechanisms underlying HFD-induced depression remain unclear. Previou...
High-fat diet (HFD) consumption is a harmful habit worldwide that can lead to various problems, including an increased risk of depression. However, the mechanisms underlying HFD-induced depression remain unclear. Previous studies have reported that a decline in microglia in the dentate gyrus, following initial microglial activation under stress, is an important mechanism mediating the pathogenesis of depression. As HFD can activate microglia, we hypothesize that dynamic changes in dentate gyrus microglia also mediate the development of depression-like behaviors under chronic HFD exposure. Our results showed that a 12-week HFD induced depression-like behaviors in mice, accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus. The reduction in microglia in the dentate gyrus of mice treated with a 12-week HFD was mediated by initial microglial activation and subsequent microglial damage. Suppressing initial microglial activation with minocycline prevented HFD-induced dentate gyrus microglial damage and decline, as well as the development of depression-like behaviors in HFD-treated mice. Furthermore, administration of lipopolysaccharide (LPS), a classical microglial stimulant that restored the number of microglia in the dentate gyrus of HFD mice, reversed the depression-like behaviors in mice given a 12-week HFD. These findings reveal a dynamic microglial response in the dentate gyrus underlying HFD-induced depression-like behaviors and suggest that modulating microglial dynamics may offer a potential strategy for preventing or treating depression caused by factors associated with high fat intake.
Functional interaction between orexin/CRF and orexin/dynorphin transmission in the infralimbic cortex modulates the stress-induced reinstatement of alcohol-seeking behavior in male and female Wistar rats.
Flores-Ramirez FJ, Martin-Fardon R
Neuropharmacology · 2026 Jun · PMID 41765280 · Full text
Stress contributes to the chronic relapsing nature of alcohol use disorder (AUD), given its ability to elicit craving and precipitate relapse, even after long periods of self-imposed abstinence. Although not thoroughly u...
Stress contributes to the chronic relapsing nature of alcohol use disorder (AUD), given its ability to elicit craving and precipitate relapse, even after long periods of self-imposed abstinence. Although not thoroughly understood, anatomical, pharmacological, and behavioral data suggest orexin (OX), corticotropin-releasing factor (CRF), and dynorphin (DYN) interact, particularly in the infralimbic cortex (IL). Functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects, rendering them vulnerable to relapse. Male and female Wistar rats were trained to self-administer 10% alcohol for 3 weeks and then made dependent via chronic intermittent alcohol vapor exposure for 6 weeks. Following extinction training (12 sessions), rats received an intra-IL microinfusion of the OX receptor antagonist suvorexant (15 μg/0.5 μl/side), the CRF receptor antagonist CP154,526 (0.6 μg/0.5 μl/side), the κ-opioid receptor antagonist nor-binaltorphimine (norBNI; 4 μg/0.5 μl/side), or a combination of suvorexant + CP154,526 or suvorexant + norBNI. Rats were then tested for footshock stress-induced reinstatement of alcohol-seeking behavior. In nondependent rats, only CP154,526 prevented the reinstatement of alcohol-seeking behavior, an effect that was reversed by suvorexant co-administration. In dependent rats, suvorexant, CP154,526, and norBNI attenuated alcohol-seeking behavior. Interestingly, the co-administration of suvorexant + CP154,526 or suvorexant + norBNI attenuated suvorexant's effect. Increases in Hcrtr1 mRNA expression in the IL were found in alcohol-dependent rats only. These results demonstrate a functional interaction between OX/CRF and OX/DYN receptor signaling in the IL in subjects with a history of alcohol dependence.
Repeated fentanyl administration impairs spatial memory, synaptic plasticity, and induces neuroinflammation in the dorsal hippocampus of rats.
Rocha-Botello G, Cruz SL, Galván EJ
Neuropharmacology · 2026 Jun · PMID 41764978 · Publisher ↗
Repeated opioid exposure, including therapeutic or illicit fentanyl (Fnt) use, disrupts the hippocampal network activity that supports learning and memory. However, the cellular mechanisms underlying these effects remain...
Repeated opioid exposure, including therapeutic or illicit fentanyl (Fnt) use, disrupts the hippocampal network activity that supports learning and memory. However, the cellular mechanisms underlying these effects remain elusive. To elucidate how Fnt alters hippocampal-dependent behavior, synaptic physiology, and neuroinflammation in the dorsal hippocampus, we conducted behavioral testing, electrophysiological recordings, and immunofluorescence analyses for GFAP, CD11b, and the inflammasome NLPR3 in rats repeatedly administered with Fnt (0.1 mg/kg, three times daily for 7 days; 19 injections). At the end of the administration protocol, Fnt reduced the exploration of relocated objects in the object location task, indicating impaired spatial memory. Extracellular recordings in acute brain slices of the dorsal hippocampus revealed that Fnt decreased the population spike amplitude of CA1 pyramidal cells, the fiber volley-fEPSP synchronization ratio, and altered the paired-pulse facilitation of glutamatergic transmission. Consistent with these findings, the magnitude of long-term potentiation (LTP) induced by theta-burst stimulation was reduced, mirroring decreased synaptic plasticity. Immunoreactivity analyses revealed increased GFAP and CD11b expression, accompanied by microglial hypertrophy and elevated NLRP3 expression in neurons and interneurons in area CA1, indicating astrogliosis and inflammasome priming. These findings indicate that repeated Fnt administration disrupts neuronal and glial homeostasis in the hippocampus.
Glucocorticoid receptor blockade reverses heroin and alcohol withdrawal-induced hyperalgesia in rats.
Skandan N, Acosta VP, Vendruscolo JCM … +2 more , McGinn MA, Vendruscolo LF
Neuropharmacology · 2026 Jun · PMID 41763299 · Full text
RATIONALE: Alcohol use disorder (AUD) and opioid use disorder (OUD) are associated with dysregulation of the hypothalamic-pituitary-adrenal axis and extrahypothalamic stress systems, including glucocorticoid receptor (GR...
RATIONALE: Alcohol use disorder (AUD) and opioid use disorder (OUD) are associated with dysregulation of the hypothalamic-pituitary-adrenal axis and extrahypothalamic stress systems, including glucocorticoid receptor (GR) signaling. Hyperalgesia is defined as an increased sensitivity to nociceptive stimuli and is a prominent symptom of alcohol and opioid withdrawal, which is hypothesized to contribute to the development and persistence of AUD and OUD and heighten relapse vulnerability. OBJECTIVE: We tested the hypothesis that GR antagonism reverses hyperalgesia during both alcohol and opioid withdrawal. METHODS: Male and female Wistar rats were either made alcohol-dependent through chronic, intermittent alcohol vapor exposure or made opioid-dependent via daily, subcutaneous heroin injections (1-6 mg/kg). Mechanical and thermal nociceptive sensitivity were assessed 6-8 h into spontaneous withdrawal using the von Frey and Hargreaves tests, respectively. RESULTS: In male rats, withdrawal from alcohol and heroin produced both mechanical and thermal hyperalgesia. The nonselective GR antagonist mifepristone reduced thermal and mechanical hyperalgesia in alcohol-dependent but not control male rats. Mifepristone reduced thermal but not mechanical sensitivity in heroin-dependent and control male rats. In female rats, alcohol withdrawal produced thermal but not mechanical hyperalgesia. Thermal hyperalgesia was reversed by mifepristone in female alcohol-dependent rats. In contrast, heroin withdrawal produced mechanical hyperalgesia that was insensitive to mifepristone but reversed by the selective GR antagonist miricorilant. CONCLUSION: These findings reveal sex- and nociception modality-specific differences in alcohol and opioid withdrawal-induced hyperalgesia and highlight GR signaling as a potential therapeutic target for managing drug withdrawal-related pain.
Sex-specific responses on alcohol intake in rodents following sCT infusion in the middle part of the paraventricular nucleus of the thalamus.
Aranäs C, Caffrey A, Edvardsson CE … +4 more , Witley S, Zhang Q, Schmidt HD, Jerlhag E
Neuropharmacology · 2026 Jun · PMID 41763298 · Publisher ↗
BACKGROUND: Long-term alcohol consumption contributes to the development of alcohol use disorder (AUD), a complex disorder with multifaceted neurobiological underpinnings. One of these is appetite-regulatory peptides, su...
BACKGROUND: Long-term alcohol consumption contributes to the development of alcohol use disorder (AUD), a complex disorder with multifaceted neurobiological underpinnings. One of these is appetite-regulatory peptides, such as amylin, where activation of the amylin receptor (AMYR) suppresses alcohol-related behaviours in rodents. Earlier research has pinpointed AMYR in the nucleus accumbens (NAc) as central for this interaction, where other brain regions most likely participate. One of these might be the middle part of the paraventricular thalamus (mid-PVT), a critical node in reward-related processes. We therefore accessed this interaction through a combination of behavioural, neurochemical, and molecular experiments. METHODS: Western Blot, immunohistochemistry, and RNAscope were utilized to identify the calcitonin receptor (CTR), the main component of AMYR, in mid-PVT. To investigate the effects of salmon calcitonin (sCT), a CTR and AMYR agonist, locally infused in the mid-PVT on alcohol-related behaviours in rodents, the intermittent alcohol drinking paradigm, locomotor stimulation test, and microdialysis setup were employed. FINDINGS: CTR was detected in the thalamus in male NMRI mice and in mid-PVT of Wistar and Sprague Dawley (SD) rats. Locally infused sCT into mid-PVT decreased alcohol intake in males (P = 0.0048), but not in female (P = 0.8982) Wistar rats. A pilot experiment indicated that CTR was co-localized with glutamatergic projections from mid-PVT to NAc in males, but not female SD rats. Moreover, in male NMRI mice, sCT into mid-PVT attenuated alcohol-induced locomotor stimulation and dopamine release in NAc. INTERPRETATION: In summary, sCT into mid-PVT suppressed alcohol-related behaviours in male rodents, potentially through CTR on glutamatergic projections to NAc.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe