Pub Date : 2026-03-12DOI: 10.1016/j.neulet.2026.138574
Cai Wang, Jian Li, Qiang Liu, Rui Yang, John H Zhang, Yun-Peng Cao, Xue-Jun Sun
{"title":"Retraction notice to \"Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer's disease\" [Neurosci. Lett. 491 (2011) 127-132].","authors":"Cai Wang, Jian Li, Qiang Liu, Rui Yang, John H Zhang, Yun-Peng Cao, Xue-Jun Sun","doi":"10.1016/j.neulet.2026.138574","DOIUrl":"10.1016/j.neulet.2026.138574","url":null,"abstract":"","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138574"},"PeriodicalIF":2.0,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147458947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1016/j.neulet.2026.138576
Yuqian Shang, Shuneng Zhong, Manxu Zheng, Na Chen, Yangyu Wang
Healthy aging is associated with changes in neural organization that may influence language production. Using task-based fNIRS, we examined cortical activation and functional connectivity during overt picture naming and sentence repetition in Mandarin speakers. Seventeen right-handed adults (10 younger, mean age = 22.1; 7 older, mean age = 58.6) completed both tasks while HbO responses were recorded over fronto-temporo-parietal cortex. Block-averaged HbO activation did not differ reliably between groups in either task. In contrast, the primary task-epoch connectivity analysis indicated stronger dorsolateral prefrontal-temporo-parietal coupling in older adults during picture naming; however, this group difference was not statistically robust in a more conservative baseline-referenced contrast. No connections survived correction for multiple comparisons during sentence repetition. These results suggest that, under relatively low-demand overt speech production, age-related differences may be more evident in network-level interactions than in mean regional activation magnitude. Task-based fNIRS may be useful for probing age-related modulation of speech-related brain networks during overt language production.
{"title":"Neural mechanisms of age-related changes in language performance: A pilot fNIRS study.","authors":"Yuqian Shang, Shuneng Zhong, Manxu Zheng, Na Chen, Yangyu Wang","doi":"10.1016/j.neulet.2026.138576","DOIUrl":"10.1016/j.neulet.2026.138576","url":null,"abstract":"<p><p>Healthy aging is associated with changes in neural organization that may influence language production. Using task-based fNIRS, we examined cortical activation and functional connectivity during overt picture naming and sentence repetition in Mandarin speakers. Seventeen right-handed adults (10 younger, mean age = 22.1; 7 older, mean age = 58.6) completed both tasks while HbO responses were recorded over fronto-temporo-parietal cortex. Block-averaged HbO activation did not differ reliably between groups in either task. In contrast, the primary task-epoch connectivity analysis indicated stronger dorsolateral prefrontal-temporo-parietal coupling in older adults during picture naming; however, this group difference was not statistically robust in a more conservative baseline-referenced contrast. No connections survived correction for multiple comparisons during sentence repetition. These results suggest that, under relatively low-demand overt speech production, age-related differences may be more evident in network-level interactions than in mean regional activation magnitude. Task-based fNIRS may be useful for probing age-related modulation of speech-related brain networks during overt language production.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138576"},"PeriodicalIF":2.0,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147458931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thoracic spinal cord stimulation (SCS) has been reported to facilitate swallowing, however the underlying brainstem mechanisms remain unclear. We developed a Gaussian-frequency, charge-imbalanced biphasic waveform designed to enhance sensory afferent drive to spinal circuits while maintaining safe charge delivery. Using an in situ perfused brainstem-spinal cord preparation of rats, which preserves intrinsic swallowing circuits and enables direct assessment of central pattern generator (CPG) outputs, we compared this waveform with a conventional fixed-frequency monophasic pulse used in clinical and experimental settings. Electrical stimulation was applied epidurally to the T8 spinal segment via a concentric electrode, and neural activity was recorded from the phrenic nerves, vagus nerves, and hypoglossal nerves under three conditions: no stimulation, monophasic stimulation, and Gaussian-frequency charge-imbalanced biphasic stimulation. Both stimulation types significantly increased swallow count, shortened the swallowing interburst interval, and enhanced swallow-related vagus nerve activity (VNA) and hypoglossal nerve activity (HNA) compared with no stimulation. However, the Gaussian-frequency waveform produced a significantly greater increase in swallow number than monophasic stimulation. Consistent with previous findings that stochastic stimulation can reduce sensory adaptation and improve detection of weak inputs, our results suggest that, once the swallowing CPG is engaged, stochastic stimulation does not primarily accelerate its rhythm but instead increases the likelihood and duration of CPG activation bouts.Thoracic SCS using this waveform may therefore provide a neuromodulatory strategy that may enhance the functional selectivity of cathodal activation within spinal circuits within spinal circuits and facilitates recruitment of brainstem swallowing networks.
{"title":"Efficacy of a Gaussian-frequency charge-imbalanced biphasic waveform for facilitating swallowing via thoracic epidural spinal cord stimulation.","authors":"In Kitamura, Mami Kaneko, Yoichiro Sugiyama, Shinya Fuse, Shigeru Hirano, Kimberly Iceman, Teresa Pitts, Takuji Koike","doi":"10.1016/j.neulet.2026.138577","DOIUrl":"10.1016/j.neulet.2026.138577","url":null,"abstract":"<p><p>Thoracic spinal cord stimulation (SCS) has been reported to facilitate swallowing, however the underlying brainstem mechanisms remain unclear. We developed a Gaussian-frequency, charge-imbalanced biphasic waveform designed to enhance sensory afferent drive to spinal circuits while maintaining safe charge delivery. Using an in situ perfused brainstem-spinal cord preparation of rats, which preserves intrinsic swallowing circuits and enables direct assessment of central pattern generator (CPG) outputs, we compared this waveform with a conventional fixed-frequency monophasic pulse used in clinical and experimental settings. Electrical stimulation was applied epidurally to the T8 spinal segment via a concentric electrode, and neural activity was recorded from the phrenic nerves, vagus nerves, and hypoglossal nerves under three conditions: no stimulation, monophasic stimulation, and Gaussian-frequency charge-imbalanced biphasic stimulation. Both stimulation types significantly increased swallow count, shortened the swallowing interburst interval, and enhanced swallow-related vagus nerve activity (VNA) and hypoglossal nerve activity (HNA) compared with no stimulation. However, the Gaussian-frequency waveform produced a significantly greater increase in swallow number than monophasic stimulation. Consistent with previous findings that stochastic stimulation can reduce sensory adaptation and improve detection of weak inputs, our results suggest that, once the swallowing CPG is engaged, stochastic stimulation does not primarily accelerate its rhythm but instead increases the likelihood and duration of CPG activation bouts.Thoracic SCS using this waveform may therefore provide a neuromodulatory strategy that may enhance the functional selectivity of cathodal activation within spinal circuits within spinal circuits and facilitates recruitment of brainstem swallowing networks.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138577"},"PeriodicalIF":2.0,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26Epub Date: 2025-12-19DOI: 10.1016/j.neulet.2025.138493
Yi Sun , Jiayu Wang , Aoyuan Zhang , Ankang Hu , Lianlian Wu
Chlorogenic acid (CGA) possesses diverse biological functions, including antioxidant, anti-inflammatory, and anti-apoptotic, both in vitro and in vivo. Recent studies have suggested that CGA also has neuroprotective effects. However, its potential to alleviate seizures and attenuate epilepsy-related neuropathology remains unclear. This study investigated the effects and underlying mechanisms of CGA in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. CGA treatment significantly reduced epileptic seizures. Nissl and NeuN immunofluorescence staining revealed that CGA also significantly reduced neuronal damage. Furthermore, CGA promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and suppressed neuroinflammation, evidenced by iNOS/IBA-1 and Arg-1/IBA-1 immunofluorescence and RT-PCR. BrdU staining revealed that CGA inhibited epilepsy-induced aberrant neurogenesis. In addition, behavioral tests showed improved cognitive performance following CGA treatment. Finally, western blot analysis indicated the activation of the Nrf2/HO-1 pathway, and Nrf2 knockdown reversed CGA’s effects. These findings suggest that CGA exerts anti-seizure and neuroprotective effects via microglial modulation through the Nrf2/HO-1 pathway.
{"title":"Chlorogenic acid exerts anti-inflammation and neuroprotective effect in pentylenetetrazole-induced epilepsy mouse model by regulating microglia polarization via Nrf2/HO-1 pathway","authors":"Yi Sun , Jiayu Wang , Aoyuan Zhang , Ankang Hu , Lianlian Wu","doi":"10.1016/j.neulet.2025.138493","DOIUrl":"10.1016/j.neulet.2025.138493","url":null,"abstract":"<div><div>Chlorogenic acid (CGA) possesses diverse biological functions, including antioxidant, anti-inflammatory, and anti-apoptotic, both <em>in vitro and in vivo</em>. Recent studies have suggested that CGA also has neuroprotective effects. However, its potential to alleviate seizures and attenuate epilepsy-related neuropathology remains unclear. This study investigated the effects and underlying mechanisms of CGA in a pentylenetetrazole (PTZ)-induced epilepsy mouse model. CGA treatment significantly reduced epileptic seizures. Nissl and NeuN immunofluorescence staining revealed that CGA also significantly reduced neuronal damage. Furthermore, CGA promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and suppressed neuroinflammation, evidenced by iNOS/IBA-1 and Arg-1/IBA-1 immunofluorescence and RT-PCR. BrdU staining revealed that CGA inhibited epilepsy-induced aberrant neurogenesis. In addition, behavioral tests showed improved cognitive performance following CGA treatment. Finally, western blot analysis indicated the activation of the Nrf2/HO-1 pathway, and Nrf2 knockdown reversed CGA’s effects. These findings suggest that CGA exerts anti-seizure and neuroprotective effects via microglial modulation through the Nrf2/HO-1 pathway.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138493"},"PeriodicalIF":2.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuropathic pain is a prevalent and debilitating chronic condition for which current treatments often provide inadequate relief. This constitutes a significant unmet clinical need, highlighting the importance of identifying novel molecular targets for more effective pharmacotherapy. Synaptic remodeling-mediated central sensitization is a key regulatory factor. Glutamate is a major excitatory transmitter in the central nervous system and binds to NMDA receptors in the postsynaptic membrane to promote synaptic remodeling. In C57 mice with spared nerve injury, it was noted that GPR17 and the GluN2A and GluN2B subunits of the NMDA receptor were elevated in the L4-L6 region of the spinal cord. Lentiviral knockdown of spinal GPR17 attenuated mechanical allodynia, suppressed astrocyte activation, and decreased levels of GluN2A and GluN2B subunits. GPR17 controls neuropathic pain, stimulates astrocyte activation, and NMDA receptor overexpression on neurons. Targeting GPR17 may represent a new therapeutic strategy for the management of neuropathic pain.
{"title":"G protein-coupled receptor 17 promotes neuropathic pain in male mice by upregulating spinal NMDAR subunit expression","authors":"Biyun Li, Xueqin Xu, Qin Xiao, Kunyu Zhang, Xiuqin Yu, Yangqiao Xiao, Shuangshuang Lu, Wenjiao Jin, Panpan Sun, Longhui Li, Chunyu Ma, Zihao Lu, Yanqiong Wu, Changbin Ke","doi":"10.1016/j.neulet.2026.138509","DOIUrl":"10.1016/j.neulet.2026.138509","url":null,"abstract":"<div><div>Neuropathic pain is a prevalent and debilitating chronic condition for which current treatments often provide inadequate relief. This constitutes a significant unmet clinical need, highlighting the importance of identifying novel molecular targets for more effective pharmacotherapy. Synaptic remodeling-mediated central sensitization is a key regulatory factor. Glutamate is a major excitatory transmitter in the central nervous system and binds to NMDA receptors in the postsynaptic membrane to promote synaptic remodeling. In C57 mice with spared nerve injury, it was noted that GPR17 and the GluN2A and GluN2B subunits of the NMDA receptor were elevated in the L4-L6 region of the spinal cord. Lentiviral knockdown of spinal GPR17 attenuated mechanical allodynia, suppressed astrocyte activation, and decreased levels of GluN2A and GluN2B subunits. GPR17 controls neuropathic pain, stimulates astrocyte activation, and NMDA receptor overexpression on neurons. Targeting GPR17 may represent a new therapeutic strategy for the management of neuropathic pain.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138509"},"PeriodicalIF":2.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26Epub Date: 2025-12-18DOI: 10.1016/j.neulet.2025.138492
Lutfi Putra Perdana , Jaime Fabillar Jr , Dara Sari Arini , Swarnalakshmi Raman , Resmi Raju , Daisuke Ikutame , Masamitsu Oshima , Keiko Miyoshi , Yoshizo Matsuka
Interleukin-10 (IL-10) is a cytokine that can exert an analgesic effect on trigeminal neuropathic pain (TNP). However, its precise mechanism remains unclear. In this study, we investigated the antinociceptive effects of recombinant IL-10 (rIL-10) in a rat model of infraorbital nerve constriction. Using male Sprague-Dawley rats, we administered rIL-10 or phosphate-buffered saline to the intra-trigeminal ganglion and observed a peak analgesic effect at 4 h post-injection in the rIL-10 group. Real-time PCR demonstrated significant upregulation of the Proopiomelanocortin (Pomc) gene in rIL-10-treated rats, with immunofluorescence staining confirming increased expression of bioactive peptide β-endorphin (β-END) in the same group. In situ hybridization assay further localized Pomc expression to satellite glial cells and neurons in the trigeminal ganglion, with β-END exhibiting a similar distribution. To elucidate the signaling mechanism, we co-administered a STAT3 inhibitor, Stattic, which abolished the analgesic effect of rIL-10, suppressed Pomc upregulation, and reduced β-END expression. These findings indicate that the STAT3 pathway is a critical mediator of rIL-10-induced analgesia, with Pomc and β-END as potential molecular effectors.
{"title":"Antinociceptive role of IL-10/STAT3 signaling in trigeminal neuropathic pain male rat model through Pomc and β-endorphin","authors":"Lutfi Putra Perdana , Jaime Fabillar Jr , Dara Sari Arini , Swarnalakshmi Raman , Resmi Raju , Daisuke Ikutame , Masamitsu Oshima , Keiko Miyoshi , Yoshizo Matsuka","doi":"10.1016/j.neulet.2025.138492","DOIUrl":"10.1016/j.neulet.2025.138492","url":null,"abstract":"<div><div>Interleukin-10 (IL-10) is a cytokine that can exert an analgesic effect on trigeminal neuropathic pain (TNP). However, its precise mechanism remains unclear. In this study, we investigated the antinociceptive effects of recombinant IL-10 (rIL-10) in a rat model of infraorbital nerve constriction. Using male Sprague-Dawley rats, we administered rIL-10 or phosphate-buffered saline to the intra-trigeminal ganglion and observed a peak analgesic effect at 4 h post-injection in the rIL-10 group. Real-time PCR demonstrated significant upregulation of the Proopiomelanocortin (<em>Pomc</em>) gene in rIL-10-treated rats, with immunofluorescence staining confirming increased expression of bioactive peptide β-endorphin (β-END) in the same group. <em>In situ</em> hybridization assay further localized <em>Pomc</em> expression to satellite glial cells and neurons in the trigeminal ganglion, with β-END exhibiting a similar distribution. To elucidate the signaling mechanism, we co-administered a STAT3 inhibitor, Stattic, which abolished the analgesic effect of rIL-10, suppressed <em>Pomc</em> upregulation, and reduced β-END expression. These findings indicate that the STAT3 pathway is a critical mediator of rIL-10-induced analgesia, with <em>Pomc</em> and β-END as potential molecular effectors.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138492"},"PeriodicalIF":2.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26Epub Date: 2025-12-21DOI: 10.1016/j.neulet.2025.138494
Anirudhya Lahiri, Lucille E Papile, Zaenab Dhari, Jake T Lustig, Evan T Lombardo, Erica R Lavoie, Pearl A Sutter, Stephen J Crocker
Dysfunction in bladder control (incontinence) is a significant comorbidity in multiple sclerosis that diminishes patients’ quality of life and is a leading cause of hospitalization. Recent evidence indicates that CNS demyelination is sufficient to induce incontinence, while bladder control is also restored following remyelination. Based on this strong association, we hypothesized that remyelination is necessary for the restoration of bladder function control after acute demyelination. To test this, we evaluated changes in bladder function in mice in which Myelin regulatory factor (Myrf) was conditionally knocked out in oligodendrocyte precursor cells (OPC)(PDGFR⍺- CreERTM, Myrffl/fl (Myrf-cKO)) and compared these with control groups during and after being subjected to cuprizone treatment. Here, we report that acute demyelination leads to bladder control dysfunction which was evidenced by significantly increased voiding behavior irrespective of genotype. However, during the remyelination phase, we observed an amelioration of incontinence in all groups, including mice in which remyelination fails (e.g. Myrf-cKO mice). These data suggest that while active demyelination can initiate loss of bladder function control, failed remyelination is not an impediment to potential adaptive changes which may facilitate restoration of proper bladder function.
{"title":"Recovery from cuprizone induced incontinence is not dependent upon remyelination","authors":"Anirudhya Lahiri, Lucille E Papile, Zaenab Dhari, Jake T Lustig, Evan T Lombardo, Erica R Lavoie, Pearl A Sutter, Stephen J Crocker","doi":"10.1016/j.neulet.2025.138494","DOIUrl":"10.1016/j.neulet.2025.138494","url":null,"abstract":"<div><div>Dysfunction in bladder control (incontinence) is a significant comorbidity in multiple sclerosis that diminishes patients’ quality of life and is a leading cause of hospitalization. Recent evidence indicates that CNS demyelination is sufficient to induce incontinence, while bladder control is also restored following remyelination. Based on this strong association, we hypothesized that remyelination is necessary for the restoration of bladder function control after acute demyelination. To test this, we evaluated changes in bladder function in mice in which Myelin regulatory factor (<em>Myrf</em>) was conditionally knocked out in oligodendrocyte precursor cells (OPC)(PDGFR⍺- CreER<sup>TM</sup>, <em>Myrf</em><sup>fl/fl</sup> (<em>Myrf</em>-cKO)) and compared these with control groups during and after being subjected to cuprizone treatment. Here, we report that acute demyelination leads to bladder control dysfunction which was evidenced by significantly increased voiding behavior irrespective of genotype. However, during the remyelination phase, we observed an amelioration of incontinence in all groups, including mice in which remyelination fails (e.g. <em>Myrf</em>-cKO mice). These data suggest that while active demyelination can initiate loss of bladder function control, failed remyelination is not an impediment to potential adaptive changes which may facilitate restoration of proper bladder function.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138494"},"PeriodicalIF":2.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.
Subjects and methods
Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.
Results
Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.
Conclusion
Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.
{"title":"Comparative effects of antidepressants on cocaine-induced hyperthermia in rats: a preclinical study","authors":"Tsuyoshi Okada , Seiji Obi , Manabu Takano , Katsutoshi Shioda , Shiro Suda","doi":"10.1016/j.neulet.2026.138508","DOIUrl":"10.1016/j.neulet.2026.138508","url":null,"abstract":"<div><h3>Purpose</h3><div>Cocaine abuse is a major public health concern and is often associated with acute hyperthermia, which can be fatal and has limited pharmacological interventions for its management. Although antidepressants are frequently prescribed to cocaine users, particularly to those with comorbid depression, their safety within this context remains unclear, as some can exacerbate the toxicity of cocaine. This study aimed to evaluate the effects of various antidepressants on cocaine-induced hyperthermia in rats to identify safer treatment options.</div></div><div><h3>Subjects and methods</h3><div>Adult male Wistar rats received intraperitoneal injections of cocaine (30 mg/kg) following pretreatment with one of the following antidepressants: mirtazapine, fluoxetine, venlafaxine, amitriptyline, or moclobemide. To elucidate the mechanism underlying the effects of mirtazapine, the selective 5-HT2A receptor antagonists ketanserin and ritanserin were also tested. Rectal temperature was measured every 30 min for up to 240 min after cocaine administration.</div></div><div><h3>Results</h3><div>Cocaine administration significantly elevated body temperature in control rats. However, pretreatment with mirtazapine significantly suppressed this hyperthermic response, presumably via central 5-HT2A receptor antagonism. Ketanserin and ritanserin similarly suppressed hyperthermia, supporting this proposed mechanism. In contrast, moclobemide exacerbated the hyperthermia, venlafaxine prolonged the hyperthermic response, and fluoxetine and amitriptyline had no significant effect on the hyperthermic response.</div></div><div><h3>Conclusion</h3><div>Mirtazapine may be a safer antidepressant option for managing depression in cocaine users because of its capacity to suppress hyperthermia without enhancing monoamine reuptake inhibition. Notably, caution should be exercised when prescribing monoamine oxidase inhibitors and SNRIs to this population. However, further clinical studies are required to validate these findings.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138508"},"PeriodicalIF":2.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26Epub Date: 2025-12-23DOI: 10.1016/j.neulet.2025.138495
Leydi Carolina González Gómez, María Clara Gravielle
GABAA receptors play a crucial role in mediating fast inhibitory neurotransmission in the central nervous system. These receptors are targets of numerous pharmacological agents used clinically to control neuronal excitability in different neurological disorders. Sustained stimulation of GABAA receptors by endogenous or exogenous modulators leads to adaptive homeostatic alterations in the receptor function. In particular, chronic benzodiazepine administration results in tolerance to most of the behavioral effects, limiting the clinical use of these drugs for long-term treatments. In previous studies, we found that prolonged exposure of rat cerebrocortical neurons to diazepam produces uncoupling of GABA/benzodiazepine site interactions and decreased expression of the GABAA receptor α1 subunit gene, mediated by a mechanism involving the activation of L-type voltage-gated calcium channels (L-VGCCs). This work aimed to further explore the molecular basis of GABAA receptor regulation induced by prolonged benzodiazepine stimulation. Our findings indicate that diazepam increases intracellular calcium levels, confirming the dependence of benzodiazepine-induced GABAA receptor regulation on calcium entry through L-VGCCs. Immunocytochemical analyses revealed that sustained diazepam treatment reduces the expression of α1-containing GABAA receptors on the cell surface, which likely impacts functional receptors. By knocking-down α1 subunit expression, we demonstrated that α1 downregulation alone results in minor, non-significant uncoupling, suggesting that additional GABAA receptor modifications contribute to the observed uncoupling. Altogether, our results suggest that persistent exposure of GABAA receptors to benzodiazepines produces uncoupling and downregulation of functional α1-containing GABAA receptors through two distinct mechanisms, both initiated by calcium influx through L-VGCCs.
{"title":"Prolonged exposure of cerebrocortical neurons to diazepam induces downregulation of surface α1-containing GABAA receptors and uncoupling of GABA/benzodiazepine site interactions through different mechanisms","authors":"Leydi Carolina González Gómez, María Clara Gravielle","doi":"10.1016/j.neulet.2025.138495","DOIUrl":"10.1016/j.neulet.2025.138495","url":null,"abstract":"<div><div>GABA<sub>A</sub> receptors play a crucial role in mediating fast inhibitory neurotransmission in the central nervous system. These receptors are targets of numerous pharmacological agents used clinically to control neuronal excitability in different neurological disorders. Sustained stimulation of GABA<sub>A</sub> receptors by endogenous or exogenous modulators leads to adaptive homeostatic alterations in the receptor function. In particular, chronic benzodiazepine administration results in tolerance to most of the behavioral effects, limiting the clinical use of these drugs for long-term treatments. In previous studies, we found that prolonged exposure of rat cerebrocortical neurons to diazepam produces uncoupling of GABA/benzodiazepine site interactions and decreased expression of the GABA<sub>A</sub> receptor α1 subunit gene, mediated by a mechanism involving the activation of L-type voltage-gated calcium channels (L-VGCCs). This work aimed to further explore the molecular basis of GABA<sub>A</sub> receptor regulation induced by prolonged benzodiazepine stimulation. Our findings indicate that diazepam increases intracellular calcium levels, confirming the dependence of benzodiazepine-induced GABA<sub>A</sub> receptor regulation on calcium entry through L-VGCCs. Immunocytochemical analyses revealed that sustained diazepam treatment reduces the expression of α1-containing GABA<sub>A</sub> receptors on the cell surface, which likely impacts functional receptors. By knocking-down α1 subunit expression, we demonstrated that α1 downregulation alone results in minor, non-significant uncoupling, suggesting that additional GABA<sub>A</sub> receptor modifications contribute to the observed uncoupling. Altogether, our results suggest that persistent exposure of GABA<sub>A</sub> receptors to benzodiazepines produces uncoupling and downregulation of functional α1-containing GABA<sub>A</sub> receptors through two distinct mechanisms, both initiated by calcium influx through L-VGCCs.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"873 ","pages":"Article 138495"},"PeriodicalIF":2.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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