Neuropharmacology[JOURNAL]
Sun
200 papers
Agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in parvalbumin-expressing neurons of the hippocampal ventral dentate gyrus.
Ye S, Xu Q, Bao L … +5 more , Hussein AB, Lu Q, Yuan X, Amin N, Fang M
Neuropharmacology · 2026 Jul · PMID 41887570 · Publisher ↗
BACKGROUND: Major depressive disorder (MDD) is highly prevalent, but some patients are refractory to conventional treatments. Mitochondrial dysfunction, impaired mitophagy, and parvalbumin (PV)-expressing hippocampal neu...
BACKGROUND: Major depressive disorder (MDD) is highly prevalent, but some patients are refractory to conventional treatments. Mitochondrial dysfunction, impaired mitophagy, and parvalbumin (PV)-expressing hippocampal neuron deficits are linked to MDD pathogenesis, while agomelatine's antidepressant mechanism involving these elements remains unclear. AIM: This study aimed to clarify whether agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in PV neurons of the hippocampal ventral dentate gyrus (vDG). METHODS: Male C57BL/6J and Pvalb-creAi14 mice underwent chronic unpredictable mild stress (CUMS) for depression modeling. Groups included Control, CUMS, CUMS + Fluoxetine (FLX), CUMS + Agomelatine (AGO), CUMS + AGO+3-Methyladenine (autophagy inhibitor), CUMS + AGO + Rapamycin (an mTORC1 inhibitor that indirectly promotes autophagy in a cell-type-dependent manner), and CUMS with vDG-targeted AAV-Beclin1 overexpression (oeBeclin1) ± AGO. Behavioral tests (TST, FST, SPT, OFT, SIT) and molecular/morphological analyses (Western blotting, IF, RT-qPCR, DHE staining, TEM, Golgi staining) were conducted. RESULTS: CUMS induced depressive-like behaviors and reduced PV neuron density. AGO's performance is no less effective than FLX. Mechanistically, it upregulated autophagy-related proteins (Beclin1, ATG5, LC3II/I) and downregulated p62. oeBeclin1 synergized with agomelatine to improve mitochondrial morphology, reduce ROS, and inhibit neuroinflammation. CONCLUSION: In conclusion, agomelatine alleviates CUMS-induced depressive-like behaviors in mice, which is associated with the promotion of mitophagy in vDG PV neurons of the hippocampus, mitigating mitochondrial damage and neuroinflammation. This uncovers a novel mechanism for its efficacy and highlights targeted mitophagy activation as a promising MDD therapeutic strategy.
The impact of prebiotic supplementation in a triple-hit rat model of schizophrenia.
Plesz SB, Szűcs KF, Ágg B … +11 more , Makra N, Ligeti B, Demeter ZO, Adlan LG, Liszli P, Szabó D, Ferdinandy P, Zádori ZS, Gáspár R, Horvath G, Kekesi G
Neuropharmacology · 2026 Jul · PMID 41887569 · Publisher ↗
Schizophrenia is associated with cognitive deficits and higher stress sensitivity, potentially related to gut-brain axis disturbances, partially due to dysbiosis. To ascertain this phenomenon, we aimed to evaluate these...
Schizophrenia is associated with cognitive deficits and higher stress sensitivity, potentially related to gut-brain axis disturbances, partially due to dysbiosis. To ascertain this phenomenon, we aimed to evaluate these behavioral phenotypes in association with microbiota profile in the triple-hit Wisket rat model of schizophrenia. Furthermore, as a bidirectional approach, the effects of clozapine (CLO) and/or prebiotic (galactooligosaccharide, B-GOS) treatment were also investigated. Male Wistar (control) and Wisket rats were treated for 3 weeks: CLO or its vehicle was administered intraperitoneally, while B-GOS or water was provided ad libitum in drinking bottle. The food-rewarded Ambitus test was used to assess cognition-related behaviors before and during the third week of the treatment. Afterwards, fecal samples were collected to analyse microbiota composition, and smooth muscle electromyography was performed to assess immobilization-induced stress response. B-GOS monotreatment resulted in the highest improvement in cognition-related parameters in Wisket model rats; however, it never reached the performance of control animals. Wisket animals showed higher vulnerability to immobilization-induced stress condition. This group-difference disappeared by each pharmacological treatment, with the most prominent effect of the CLO + B-GOS combination treatment. β-diversity analysis revealed an overall compositional difference of fecal microbiota between treatment groups. Several taxa associated with schizophrenia-model or treatment were significantly correlated with behavioral parameters. Consistent with clinical findings, cognitive impairment with increased stress sensitivity were highlighted in Wisket model rats. To our knowledge, this is the first study on B-GOS prebiotic in a triple-hit schizophrenia model, suggesting microbiome-targeted therapy may aid some schizophrenia-related symptoms.
Novel mechanism of hypidone hydrochloride (YL-0919) in Parkinson's disease: inhibiting neuronal ferroptosis by targeting the Sigma1R-PI3K-AKT-ACSL4 axis.
Huang M, Lyu Y, Sun J … +9 more , Du C, Chen J, Lu J, Li G, Wang Z, Zhang J, Li Y, Li Y, Han G
Neuropharmacology · 2026 Jul · PMID 41887568 · Publisher ↗
Increasing evidence suggests antidepressants possess neuroprotective and anti-inflammatory properties. Hypidone hydrochloride (YL-0919), a novel antidepressant with rapid antidepressant effects currently in Phase II clin...
Increasing evidence suggests antidepressants possess neuroprotective and anti-inflammatory properties. Hypidone hydrochloride (YL-0919), a novel antidepressant with rapid antidepressant effects currently in Phase II clinical trials, exhibits antidepressant, anxiolytic, and cognitive-enhancing activities, but its potential role in Parkinson's disease (PD)-related neuronal damage remains unexplored. Here, we investigated the effects of YL-0919 on an MPTP-induced PD mouse model and on MPP-induced neuronal damage model. This study demonstrated that YL-0919 ameliorated PD pathology in mice, as evidenced by reduced symptom severity, attenuated inflammatory response, diminished neuronal damage, and improved motor dysfunction. Furthermore, YL-0919 reduced ferroptosis in MPP-induced SH-SY5Y and PC12 cells by reduced Fe staining, intracellular ROS, lipid peroxidation levels, and mitochondrial membrane potential. Mechanistically, YL-0919 inhibited neuronal ferroptosis by regulating the Sigma1R-PI3K-AKT-ACSL4 axis, thereby alleviating neurological impairment. These findings reveal a novel neuroprotective mechanism of YL-0919 in PD, highlighting the Sigma1R-PI3K-AKT-ACSL4 axis as a promising therapeutic target for mitigating PD symptoms through ferroptosis inhibition.
A bioluminescent ratiometric sensor for the measurement of extracellular ATP concentration in inflammation and cancer.
Tarantini M, Falzoni S, Carotti M … +6 more , Schio S, Redolfi N, Scano M, Pizzo P, Sandonà D, Di Virgilio F
Neuropharmacology · 2026 Jul · PMID 41881299 · Publisher ↗
ATP is not only the key intracellular energy currency but also a ubiquitous extracellular messenger. Large increases in its extracellular concentration occur at sites of infection and inflammation, in the tumor microenvi...
ATP is not only the key intracellular energy currency but also a ubiquitous extracellular messenger. Large increases in its extracellular concentration occur at sites of infection and inflammation, in the tumor microenvironment and virtually in any disease states. However, the accurate measurement of the extracellular ATP (eATP) is still a crucial issue. We describe here a novel ratiometric bioluminescent indicator suitable to accurately measure the eATP concentration in vitro and in vivo. This sensor, named pmeLUC/nilla, is an evolution of the pmeLUC probe previously developed by us, and allows faithful monitoring of eATP changes, independently of the level of probe expression, thus overcoming a key limitation of existing probes. The pmeLUC/nilla consists of two luciferases expressed as a polycistronic mRNA. PmeLUC, the real ATP sensor, is synthetized into the endoplasmic reticulum, delivered to the cell surface and anchored on the plasma membrane. The Renilla luciferase, which is ATP insensitive, is translated thanks to an internal ribosomal binding site, and remains cytosolic. The luminescence coming from pmeLUC is normalized by the signal from the Renilla luciferase. The performance of the sensors was analyzed in vitro, in different cell types and upon the application of various stimuli. Moreover, its ability to monitor eATP in the tumor microenvironment was assessed in mice. Our findings demonstrate the capability of pmeLUC/nilla for real-time and precise monitoring of eATP dynamics both in vitro and in vivo. This sensor could pave the way for advanced luminescent diagnostics, enhancing our understanding and detection of inflammation and cancer.
P2X7 receptor or TNAP genetic blockade prevents the reduction of neuronal CTCF detected in tauopathy.
Aivar P, Sebastián-Serrano Á, Vincelle-Nieto Á … +5 more , Collado-Cantero AC, Ouro-Corredera D, Soria-Tobar L, Reyes-Palomares A, Díaz-Hernández M
Neuropharmacology · 2026 Jul · PMID 41881298 · Publisher ↗
Intraneuronal aggregates assembled by hyperphosphorylated Tau protein are a common feature of a neurodegenerative disease family, namely Tauopathies. Recent studies have revealed that the ionotropic purinergic receptor P...
Intraneuronal aggregates assembled by hyperphosphorylated Tau protein are a common feature of a neurodegenerative disease family, namely Tauopathies. Recent studies have revealed that the ionotropic purinergic receptor P2X7 (P2X7R) and the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) are upregulated in patients with tauopathies. Despite the molecular mechanisms underlying their upregulation remaining unknown, several studies suggest that genetic or pharmacological blocking of both proteins may represent a promising therapeutic strategy. Here, we performed transcriptomic analyses of bulk RNA-seq data from human cortical samples and revealed altered activity of multiple transcription factors (TFs) in tauopathy patients. Among the most affected TFs, we focused on the chromatin organizer CCCTC-binding factor (CTCF), as it was the only one that bound both the P2X7R and TNAP promoters. Gene expression deconvolution analyses revealed altered CTCF expression in both neuronal and glial populations from tauopathy patients. Consistently, immunofluorescence analyses in P301S mice, a tauopathy mouse model, showed a significant reduction in neuronal CTCF expression and a substantial increase in the number of glial cells with CTCF labelling. In vitro studies using neuroblastoma N2a cells confirmed that CTCF overexpression caused a transcriptional upregulation of both P2X7R and TNAP. Moreover, the fact that P2X7R activation or TNAP blockade decreases CTCF nuclear translocation suggests a bidirectional regulation. In line with these findings, we found that selective genetic P2X7R depletion or, unexpectedly, TNAP heterozygosity prevented the reduction of neuronal CTCF expression in P301S mice. Altogether, these data suggest that the newly identified TNAP/P2X7R/CTCF signaling axis is a crucial molecular mechanism underlying tauopathies.
N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in helpless mice: a comparative study with S-ketamine.
de Sousa-Silva AN, Moura CA, de Oliveira Torres CI … +9 more , Marques VB, do Nascimento Silva JM, Lobão-Soares B, Ruschi Silva S, Galvão-Coelho NL, Palhano-Fontes F, Araújo DB, da Silva ED, Gavioli EC
Neuropharmacology · 2026 Jul · PMID 41881297 · Publisher ↗
N,N-dimethyltryptamine (DMT) is an naturally occurring indoleamine with hallucinogenic and antidepressant effects in humans. Here, we compared the effects of DMT and S-ketamine, a fast-acting antidepressant, in helpless...
N,N-dimethyltryptamine (DMT) is an naturally occurring indoleamine with hallucinogenic and antidepressant effects in humans. Here, we compared the effects of DMT and S-ketamine, a fast-acting antidepressant, in helpless mice. To induce helplessness, male single and group-housed mice were exposed to inescapable footshock stress; only helpless animals were subsequently treated with S-ketamine 10 or 30 mg/kg (ip), DMT 10 or 25 mg/kg (ip), or vehicle and tested in behavioral assays. In depressive-related behavioral tests, S-ketamine and DMT (both at 10 mg/kg), only in group-housed mice, 24 h after administration, reversed escape deficits and reduced escape latency in the learned helplessness model. In helpless single-housed mice, 5 days after drug administration, both compounds (at 10 mg/kg) prevented stress-induced anhedonia in the sucrose preference test. In the tail suspension test, DMT (10 mg/kg) reduced immobility up to 8 days post-injection, whereas the effects of S-ketamine (30 mg/kg) lasted up to 30 h after injection. In anxiety-related behavioral tests, DMT (10 mg/kg), but not S-ketamine, reversed stress-induced hypolocomotion in the open field test, and increased exploration in open arms in the elevated plus-maze up to 5 days post-administration. However, in the novelty-suppressed feeding behavior, at 8 days after drug administration, neither DMT nor S-ketamine altered mouse behavior. Collectively, DMT is as effective as S-ketamine in producing rapid and long-lasting antidepressant effects in helpless mice. Present data also suggest anxiolytic-like effects for DMT. Ultimately, main findings highlight the transdiagnostic therapeutic potential of DMT for stress-related disorders.
Protective effects of adenosine A2B receptor antagonism in a cuprizone-induced demyelination model.
Cherchi F, Venturini M, Frulloni L … +8 more , Panozzi F, Magni G, Santalmasi C, Maestrelli C, Giovannini MG, Coppi E, Lana D, Pugliese AM
Neuropharmacology · 2026 Jul · PMID 41881296 · Publisher ↗
Demyelinating diseases are characterized by the progressive loss of myelin in the central nervous system (CNS). Myelin protection can be achieved by fostering the differentiation of oligodendrocyte progenitor cells to ma...
Demyelinating diseases are characterized by the progressive loss of myelin in the central nervous system (CNS). Myelin protection can be achieved by fostering the differentiation of oligodendrocyte progenitor cells to mature oligodendrocytes, the only myelinating cells in the brain. Oligodendrocytes maturation is sustained, among others, by the neuromodulator adenosine through the activation of its specific receptors: A, A, A, A, all expressed in the brain on neurons and glial cells. The role of A receptors (A2BRs) in a cuprizone-induced demyelination model in male C57BL/6 mice was investigated by administering the selective A2BR agonist BAY60-6583 or antagonist PSB 603 during the last 2 weeks of a 5-week cuprizone-based diet. We performed body weight evaluation, behavioural tests and immunofluorescence analysis. Cuprizone-fed mice showed a significant decrease in body weight gain, a motor impairment and a reduced spontaneous mobility. These effects were associated with a decrease in myelin levels, a reactive astrogliosis and microgliosis in corpus callosum medialis, striatum and motor cortex. PSB 603, was able to prevent cuprizone effects on glia, whereas both compounds promoted a significant recovery in motor deficits. The antagonism of A2BRs might represent an attractive strategy to alleviate myelin damage and glial activation in the CNS under conditions of demyelination.
Acute and persistent sex-dependent disruptions of sleep-wake architecture induced by fentanyl self-administration in mice.
Delorme TC, Vilca SJ, Logan RW
Neuropharmacology · 2026 Jul · PMID 41881295 · Full text
Chronic opioid use is associated with profound sleep disturbances that may contribute to relapse in opioid use disorder (OUD). However, how opioid self-administration and abstinence alter sleep architecture in a sex-depe...
Chronic opioid use is associated with profound sleep disturbances that may contribute to relapse in opioid use disorder (OUD). However, how opioid self-administration and abstinence alter sleep architecture in a sex-dependent manner remains poorly understood. Here, we examined the effects of volitional fentanyl intravenous self-administration (IVSA) on sleep-wake architecture in male and female mice across drug-taking and abstinence phases. Continuous home-cage monitoring revealed sex differences in baseline sleep, with females exhibiting increased wakefulness and reduced NREM sleep relative to males across conditions. Fentanyl IVSA increased dark-phase NREM sleep following self-administration sessions, whereas abstinence was characterized by a persistent reduction in REM sleep accompanied by increased REM bout frequency, indicative of REM fragmentation. Correlational analyses between sleep architecture and IVSA behavior revealed that higher fentanyl intake was associated with reduced sleep, particularly in females, in contrast to the positive sleep-intake relationship observed in saline controls. Principal component analysis identified a primary sleep component that captured fentanyl-related alterations in sleep-behavior relationships and a secondary component reflecting sex-dependent variation in sleep architecture. Together, these findings demonstrate that fentanyl self-administration induces both acute and enduring, sex-specific disruptions in sleep architecture that persist into abstinence and are associated with drug-seeking behavior. These results highlight sleep as a potential mechanistic contributor to relapse vulnerability and a promising therapeutic target in OUD.
Annexin A1 and its N-terminal peptide Ac regulate dopaminergic degeneration and neuroinflammation in a 6-OHDA model of Parkinson's disease.
de Souza Ferreira LP, da Silva RA, Janisset NRLL … +9 more , da Silva Alves A, Almeida JS, Vieira RR, Santos DD, de Oliva SU, Oliani SM, Cruz FC, Dati LMM, Gil CD
Neuropharmacology · 2026 Jul · PMID 41881294 · Publisher ↗
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, and growing evidence highlights neuroinflammation as a key contributor to disease progression. Annexin A1 (AnxA1), a glu...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, and growing evidence highlights neuroinflammation as a key contributor to disease progression. Annexin A1 (AnxA1), a glucocorticoid-regulated protein with anti-inflammatory and pro-resolving functions, and its N-terminal peptide Ac have shown neuroprotective potential, but the mechanisms underlying their effects in PD remain unclear. Here, we investigated the effects of AnxA1 and Ac in a 6-hydroxydopamine (6-OHDA) mouse model of PD using C57BL/6 wild-type (AnxA1) and AnxA1 knockout (AnxA1) mice. Animals received a unilateral 6-OHDA injection into the striatum, followed by intraperitoneal injection of Ac or saline. Motor behavior, dopaminergic neuron survival, cytokine levels, and glial changes were analyzed. Ac improved motor performance and protected against 6-OHDA-induced dopaminergic degeneration in the striatum and substantia nigra (SN) of AnxA1 mice, preventing the loss of tyrosine hydroxylase (TH) neurons. These protective effects were reduced in AnxA1 mice. Ac also modulated neuroinflammation in a genotype-dependent manner, increasing anti-inflammatory cytokines and limiting pro-inflammatory mediators in the SN of AnxA1 animals. In females, genetic deletion of AnxA1 led to reduced TH expression, impaired behavioral recovery, and disruption of the estrous cycle. Overall, Ac confers neuroprotection through AnxA1-dependent regulation of neuroinflammation, dopaminergic integrity, and hormonal balance, supporting its potential as a therapeutic target in PD.
Corrigendum to "Exploring the role of ghrelin and des-acyl ghrelin in chemotherapy-induced nausea and vomiting" [Neuropharmacology 251 (2024) 109919].
Yang L, Kung CJS, Lu Z … +7 more , Liu JYH, Ngan MP, Sakai T, Sakata I, Chan SW, Tu L, Rudd JA
Neuropharmacology · 2026 Jul · PMID 41876302 · Publisher ↗
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Effects of Npy1r limbic conditional knock-out on adipose tissue metabolism.
Einaudi G, Oberto A, Bertocchi I … +7 more , Aimaretti E, Ferreira Alves G, Porchietto E, Cifani C, Micioni Di Bonaventura MV, Collino M, Chiazza F
Neuropharmacology · 2026 Jul · PMID 41866109 · Publisher ↗
Neuropeptide Y (NPY) is a key regulator of energy homeostasis, acting through various receptor subtypes in both central and peripheral systems. Increasing interest has been directed toward exploiting NPY as a pharmacolog...
Neuropeptide Y (NPY) is a key regulator of energy homeostasis, acting through various receptor subtypes in both central and peripheral systems. Increasing interest has been directed toward exploiting NPY as a pharmacological target in obesity. While the orexigenic role of NPY in the hypothalamus is well established, its downstream effects on peripheral metabolism remain less defined, particularly when perturbations to the system are introduced. Previously, we observed that female mice with limbic NPY-Y1 receptor gene (Npy1r) knockout (KO) under different dietary conditions (standard, SD, or high-fat diet, HFD) accumulated more subcutaneous white adipose tissue (WAT) compared to wild-type in the absence of gonadal hormones, despite no changes in food intake. To deepen the mechanisms underlying these effects, we conducted molecular analyses on WAT of these mice. We found that Npy gene expression was upregulated in WAT of HFD-fed mice, regardless of genotype. However, NPY peptide levels were reduced in both KO and HFD groups, suggesting post-transcriptional regulation of NPY under metabolic stress. NPY-Y2 receptor gene (Npy2r) expression in WAT was significantly increased in both KO and HFD while Npy1r expression in WAT remained unchanged across groups. Genes involved in WAT metabolism were similarly upregulated in both KO and HFD mice, indicating that limbic Npy1r KO mimics some of the metabolic effects induced by HFD. Correlation analysis suggests that dysregulated NPY signalling may promote increased lipid storage and reduce energy expenditure. Overall, these findings highlight the complex interplay between central and peripheral NPY signalling emphasizing the importance of caution when investigating therapeutic strategies targeting single NPY receptors. Overall, these findings highlight the complex interplay between central Npy1r signalling and peripheral adipose tissue regulation. They also emphasize the importance of caution when investigating new therapeutic strategies targeting single NPY receptors, as central interventions may provoke maladaptive metabolic responses in peripheral tissues.
c/EBPβ-driven Uchl3-mediated deubiquitination of TRPV1 promotes neuropathic pain by inducing mitochondrial fission in male rats.
Qiang Z, Sun D, Lei Q … +4 more , Guan R, Cai J, Wang D, Fang B
Neuropharmacology · 2026 Jul · PMID 41864557 · Publisher ↗
This study investigates the mechanism of the TRPV1 channel in neuropathic pain (NP), focusing on the c/EBPβ/Uchl3/TRPV1 axis and mitochondrial dynamics. Using male rats chronic constriction injury (CCI) model and an LPS-...
This study investigates the mechanism of the TRPV1 channel in neuropathic pain (NP), focusing on the c/EBPβ/Uchl3/TRPV1 axis and mitochondrial dynamics. Using male rats chronic constriction injury (CCI) model and an LPS-induced dorsal root ganglion (DRG) cell model, we measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), assessed expression changes of related molecules via Real-time quantitative reverse transcription PCR (RT-qPCR) and Western blot, observed mitochondrial fission via transmission electron microscopy (TEM) and Tomm20 immunofluorescence, evaluated mitochondrial function via JC-1 and MitoSOX, and examined neuronal excitability via calcium imaging. Co-immunoprecipitation (Co-IP) confirmed Uchl3-TRPV1 binding, and ubiquitination assay combined with Cycloheximide (CHX) chase and proteasome inhibition assays demonstrated that Uchl3 inhibits TRPV1 degradation via deubiquitination. Luciferase and Chromatin immunoprecipitation (ChIP) assays verified c/EBPβ as a transcriptional activator of Uchl3. Results showed that TRPV1 activation promoted mitochondrial fission, dysfunction, and neuronal excitability, driving NP. Uchl3 stabilized TRPV1 by removing its ubiquitination, altering mitochondrial dynamics. c/EBPβ transcriptionally upregulated Uchl3, forming a regulatory cascade. Intrathecal si-c/EBPβ in CCI rats downregulated c/EBPβ, Uchl3, and TRPV1, restored mitochondrial homeostasis, and alleviated pain behavior. In conclusion, the c/EBPβ/Uchl3/TRPV1 pathway regulates NP through mitochondrial dynamics in male rats, presenting a novel therapeutic target for NP treatment.
Aggression after intermittent ethanol intoxication in mice: Sex differences and modulation via medial amygdala relaxin-3/RXFP3 signaling.
Zahran MA, Mañas-Ojeda A, Sánchez MN … +3 more , Gundlach AL, Olucha-Bordonau FE, Castillo-Gómez E
Neuropharmacology · 2026 Jul · PMID 41856271 · Publisher ↗
Alcohol consumption is strongly associated with aggression and violence in humans, yet the underlying neurobiological mechanisms within key aggression circuits remain poorly understood. In this preclinical study, we exam...
Alcohol consumption is strongly associated with aggression and violence in humans, yet the underlying neurobiological mechanisms within key aggression circuits remain poorly understood. In this preclinical study, we examined the effects of intermittent alcohol intoxication on dominance and aggressive behaviors in mice, focusing on sex differences and the potential involvement of the nucleus incertus relaxin-3/relaxin-family peptide receptor 3 (RXFP3) signaling pathway. Using an intermittent ethanol-intoxication protocol, we observed that male mice displayed a transient increase in dominance and aggressive behaviors during acute abstinence, as measured by the tube-dominance and resident-intruder tests, whereas female mice displayed heightened defensive responses. Distinct patterns of neural activation across brain regions, reflected by c-Fos protein expression, were associated with aggression in males, including decreased expression in the medial amygdala (MeA) and increased expression in the ventromedial hypothalamus (VMH), consistent with an established MeA-VMH based aggression circuit. Additionally, the levels of relaxin-3 immunoreactivity in MeA nerve fibers increased in parallel with behavioral recovery, suggesting a modulatory role of relaxin-3/RXFP3 signaling. To test this hypothesis, we bilaterally injected an adeno-associated viral (AAV) vector expressing the selective RXFP3 agonist, R3/I5, into the MeA of male mice. Notably, this chronic localized R3/I5 treatment significantly reduced dominance and aggressive behaviors both before and after alcohol intoxication. Together, these data demonstrate that relaxin-3/RXFP3 signaling in the MeA counteracts alcohol-related aggression in male mice, pointing to this pathway as a potential target for treating impulsive violence associated with alcohol intoxication in humans.
2-Phenyl-3-(phenylselanyl)benzofuran attenuates depressive-like behavior and memory deficits induced by subchronic glucocorticoid exposure in female Swiss mice: role of redox and neurochemical mechanisms.
Strelow DN, Paim MP, Rech TDST … +6 more , Magalhães LS, de Mello JE, Spanevello R, Neto JSS, Brüning CA, Bortolatto CF
Neuropharmacology · 2026 Jul · PMID 41856270 · Publisher ↗
Preclinical studies are valuable tools for screening new drugs, and reports suggest that the administration of glucocorticoids, such as dexamethasone (DEX), can induce neurochemical and behavioral changes linked to depre...
Preclinical studies are valuable tools for screening new drugs, and reports suggest that the administration of glucocorticoids, such as dexamethasone (DEX), can induce neurochemical and behavioral changes linked to depression and memory deficits. The organoselenium compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) has demonstrated antidepressant-like effects and protection against memory impairments in previous studies. The present study investigated the impact of repeated SeBZF1 administration on a subchronic DEX administration protocol in female Swiss mice. The animals received daily intraperitoneal injections of DEX (2 mg/kg) or its vehicle for 21 days. In the last 7 days of the protocol, the compound SeBZF1 (1 or 5 mg/kg) or its vehicle was administered intragastrically. The 1st set revealed that SeBZF1 attenuated the increase in immobility time in the tail suspension test and the memory decline in the Y-maze test induced by DEX. The 2nd set confirmed the actions of SeBZF1 by the forced swimming test and through the object recognition test. Furthermore, SeBZF1 reduced the reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels induced by DEX administration in the prefrontal cortex and reduced ROS levels in the hippocampus. In addition, treatment with the compound modulated the monoamine oxidase A activity in the hypothalamus and acetylcholinesterase in the hippocampus. In summary, the present study elucidates the promising action of repeated SeBZF1 treatment in an experimental model of subchronic DEX administration in female Swiss mice.
Bacoside-A enhances temozolomide-induced cytotoxicity in U87MG glioblastoma cells via ROS-mediated apoptosis and EGFR/MAPK inhibition.
Mohammed Unais AK, Aparna A, Mariya KS … +1 more , Viswanadha VP
Neuropharmacology · 2026 Jul · PMID 41839256 · Publisher ↗
Temozolomide (TMZ) is the primary chemotherapeutic agent for glioblastoma multiforme (GBM), but its effectiveness is limited by resistance, recurrence, and toxicity. Combining natural compounds with TMZ is a promising ap...
Temozolomide (TMZ) is the primary chemotherapeutic agent for glioblastoma multiforme (GBM), but its effectiveness is limited by resistance, recurrence, and toxicity. Combining natural compounds with TMZ is a promising approach to overcome these challenges. Bacoside-A, a brain tonic derived from Bacopa monnieri with proven anticancer properties, was evaluated for its chemotherapeutic potential in U87MG cells. Our study demonstrates that the combination of Bacoside-A and TMZ significantly enhanced intracellular TMZ accumulation and promoted ROS-mediated apoptosis through Ca influx, mitochondrial membrane depolarization, and subsequent cell death by Apoptosis. Additionally, inhibition of EGFR-driven MAPK signalling and suppression of NF-κB nuclear translocation were observed, highlighting modulation of key survival pathways. These findings suggest that Bacoside-A potentiates TMZ efficacy while enabling dose reduction, thereby minimizing toxicity. Overall, this combinatorial approach provides mechanistic insights and a potential therapeutic strategy for improving GBM treatment outcomes.
Differential effects of cariprazine, LY379268 and donepezil on EEG oscillations and auditory steady-state response in MK-801-treated rats: relevance for schizophrenia drug development.
Adraoui FW, Violas M, Herbel H … +9 more , Viardot G, Hettak K, Tugler S, Chassignolle M, Delpy E, Maurin A, L'Hostis P, Rochelle CD, Carvalho K
Neuropharmacology · 2026 Jul · PMID 41839255 · Publisher ↗
Treating patients affected by schizophrenia (SZ) remains highly challenging for drug developers. While available antipsychotics mostly reduce positive symptoms, their effects on cognitive and social deficits as well as t...
Treating patients affected by schizophrenia (SZ) remains highly challenging for drug developers. While available antipsychotics mostly reduce positive symptoms, their effects on cognitive and social deficits as well as their underlying pathophysiology remain insufficient. Disinhibition in SZ patients' cortex is considered a key player in the genesis of these symptoms and would result from N-methyl-D-aspartate receptor (NMDAr) hypofunction on interneurons. Besides, electroencephalography-based biomarkers of these mechanisms including spontaneous and evoked gamma oscillations have been highlighted. These strongly depend on NMDAr function, associate with symptoms and therefore represent translational tools for drug development. However, reversing these circuit abnormalities is challenging for the field and finding drugs engaging them would constitute a major milestone. Here, we tested three different drugs whose features attract scientists for restoration of excitation/inhibition balance: cariprazine (D2/D3 receptor partial agonist and 5-HT receptor antagonist), LY379268 (mGlur2/3 receptor agonist) and donepezil (acetylcholinesterase inhibitor). We investigated their effects on spontaneous oscillations and auditory steady-state responses (ASSR, measuring evoked gamma oscillations) in a rat model of SZ induced by MK-801, a selective NMDAr blocker. MK-801 increased locomotor activity, impaired spontaneous and evoked gamma oscillations and altered spontaneous oscillations in delta, alpha and beta frequencies of male Sprague Dawley rats. Remarkably, both cariprazine and LY379268 normalized spontaneous gamma oscillations. Moreover, cariprazine normalized alpha and beta waves and LY379268 selectively corrected delta activity. Interestingly, only cariprazine mitigated the ASSR deficit. These differential normalization profiles, including cariprazine's unique broad-spectrum signature, reveal distinct patterns of circuit engagement and provide a translational pharmaco-EEG framework for circuit-level target engagement in SZ drug development.
Substance P/Neurokinin-1 receptor signaling exhibits sex-specific regulation of inhibitory transmission in the central amygdala.
Gashi L, Lubec J, Daneyshar BH … +2 more , Steinkellner T, Khom S
Neuropharmacology · 2026 Jul · PMID 41833601 · Publisher ↗
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Chronic morphine differentially impacts glutamatergic synaptic plasticity in the ventral tegmental area of adult versus adolescent mice.
Edwards JG, Ostlund I, Von Gunten M
Neuropharmacology · 2026 Aug · PMID 41831711 · Full text
Opioids mediate the majority of drug overdose-related deaths in the United States. Opioid-induces addictive behaviors in part via manipulation of excitatory synaptic plasticity of ventral tegmental area (VTA) dopamine ce...
Opioids mediate the majority of drug overdose-related deaths in the United States. Opioid-induces addictive behaviors in part via manipulation of excitatory synaptic plasticity of ventral tegmental area (VTA) dopamine cells by targeting presynaptic mu opioid receptors (MORs). Recent data demonstrate VTA GABAergic cells also exhibit excitatory long-term depression (LTD) plasticity that is cannabis susceptible. Here we identify expression of presynaptic MORs at excitatory inputs to VTA GABA cells of male/female adolescent and adult mice using electrophysiology, motivating further examination of morphine impact on synaptic plasticity of these understudied cells. Long-term (7-10 days) intraperitoneal injection of morphine eliminated both LTD and MOR agonist-induced synaptic depression in adolescent mice. Surprisingly, in adult mice chronic morphine eliminated LTD in only ∼50% of VTA GABA cells. Seven-day withdrawal following morphine treatment reversed LTD elimination in all adolescents GABA cells, but not in adults. Next, as LTD is cannabinoid receptor 1 (CB1)-dependent and endogenous opioid and cannabinoid systems have signaling overlap, we examined MOR influence on LTD. While MOR antagonist naloxone did not block LTD, pre-exposure of MOR agonist DAMGO occluded LTD, suggesting CB1 and MOR crosstalk. Collectively, this demonstrates morphine alteration of VTA GABA cell function and plasticity that potentially correlates to dependence and withdrawal, as well as age-dependent morphine impact. Further examination of opioid dependence mediated by the inhibitory reward circuit that considers age-dependence will be essential when considering targets for therapeutic interventions aimed at mitigating opioid addiction.
Exploring the role of ventrolateral periaqueductal gray in remifentanil-induced postoperative hyperalgesia.
Han H, Sun B, Li L … +6 more , Liu Y, Zhang H, Li B, Yu L, Yu J, Ling Y
Neuropharmacology · 2026 Jul · PMID 41831710 · Publisher ↗
Remifentanil-induced postoperative hyperalgesia (RIH) delays recovery, prolongs hospitalization, and may contribute to chronic pain. The ventrolateral periaqueductal gray (vlPAG) is a critical area for processing pain an...
Remifentanil-induced postoperative hyperalgesia (RIH) delays recovery, prolongs hospitalization, and may contribute to chronic pain. The ventrolateral periaqueductal gray (vlPAG) is a critical area for processing pain and supporting opioid-based pain relief. Inside this region, glutamate (Glu) neurons and γ-aminobutyric acid (GABA) neurons work against each other to control pain signals. However, their specific roles and underlying mechanisms in RIH remain unclear. In this study, a RIH model was established by using incisional pain mice combined with continuous infusion of remifentanil. The results indicated that RIH mice showed a significant decrease in mechanical pain thresholds in both hind paws, and this hypersensitivity only occurred under the condition of remifentanil infusion combined with surgical trauma. The expression of immediate early protein (c-Fos) in the vlPAG was significantly upregulated; calcium signal recording showed that both vlPAG-Glu and vlPAG-GABA neurons were involved in the regulation of RIH. Chemical genetic activation of vlPAG-Glu or inhibition of vlPAG-GABA could alleviate hypersensitivity. Patch clamp results showed that vlPAG-Glu in RIH mice exhibited synchronous enhancement of postsynaptic function and intrinsic excitability, while vlPAG-GABA showed increased intrinsic excitability and reduced presynaptic inhibition. Therefore, these findings strongly suggest that RIH simultaneously excites vlPAG-Glu and vlPAG-GABA neurons, the final behavioral output depends on the relative balance of the activities of these two types of neurons. Artificial activation of vlPAG-Glu or inhibition of vlPAG-GABA can effectively alleviate hypersensitivity behavior. This study provides new ideas and theoretical basis for clinical intervention strategies for RIH.
Disruption of psychostimulant-associated memories by single, low dose ketamine in rats.
Gonzalez AE, Ramos JD, Anderson Z … +5 more , Sewell CM, Modaberi S, Hentges ST, Brown TE, Sorg BA
Neuropharmacology · 2026 Jul · PMID 41825507 · Full text
Cocaine and methamphetamine use disorders pose public health concerns due to the high propensity for relapse driven by persistent drug-associated memories. Output from the medial prefrontal cortex (mPFC) regulates relaps...
Cocaine and methamphetamine use disorders pose public health concerns due to the high propensity for relapse driven by persistent drug-associated memories. Output from the medial prefrontal cortex (mPFC) regulates relapse and is controlled by parvalbumin (PV) interneurons, which are surrounded by perineuronal nets (PNNs) that support precise PV neuron firing. We previously showed that removal of mPFC PNNs, which reduces PV firing, disrupted reconsolidation of a cocaine self-administration memory when rats were given a novel, but not familiar, memory retrieval session. Ketamine rapidly suppresses PV neuron output, so we tested whether a single low dose (6 mg/kg) administered before or after a familiar or novel memory retrieval session altered cocaine cue reinstatement. Ketamine given prior to the novel, but not familiar, retrieval session reduced cue reinstatement in male Sprague-Dawley rats. In addition, both ketamine treatments combined with a novel retrieval session reduced PNN intensity around PV neurons after cue reinstatement, suggesting that PNN decreases may be unrelated to reinstatement. However, ketamine reduced the number of c-Fos-activated PV neurons immediately after the novel memory retrieval session, indicating that ketamine may reduce reinstatement through reduced PV neuron function at the time of memory retrieval. Ketamine given just prior to a novel memory retrieval session also reduced cue-induced reinstatement in rats trained for methamphetamine, but not fentanyl or sucrose self-administration. Collectively, these studies show that a single, low dose of ketamine combined with a novel memory retrieval reduces psychostimulant-seeking behavior, and may help delineate the mechanisms for ketamine-reduced relapse in psychostimulant use disorders.
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