Pub Date : 2025-02-22DOI: 10.1016/j.neuropharm.2025.110383
Man Wang, Guimin Jin, Tingting Duan, Run Li, Yubin Gao, Ming Yu, Yuhao Xu
Depression is a globally prevalent emotional disorder with a complex pathophysiology. Microglia are resident immune cells in the central nervous system, playing crucial roles in regulating inflammation, synaptic plasticity, immune phagocytosis, and other functions, thereby exerting significant impacts on neuropsychiatric disorders like depression. Increasing research indicates that abnormal phagocytic function of microglia in the brain is involved in depression, showing excessive or insufficient phagocytosis in different states. Here, we have provided a review of the signaling molecules involved in microglial phagocytosis in depression, including "eat me" signals such as phosphatidylserine (PS), complement, and "don't eat me" signals such as CD47, CD200 and related receptors. Furthermore, we discuss the regulatory effects of existing pharmaceuticals and dietary nutrients on microglial phagocytosis in depression, emphasizing the need for tailored modulation based on the varying phagocytic states of microglia. This review aims to facilitate a deeper understanding of the role of microglial phagocytosis in depression and provide a roadmap for potential therapeutic strategies for depression targeting microglial phagocytosis.
{"title":"Microglial Phagocytosis and Regulatory Mechanisms: Key Players in the Pathophysiology of Depression.","authors":"Man Wang, Guimin Jin, Tingting Duan, Run Li, Yubin Gao, Ming Yu, Yuhao Xu","doi":"10.1016/j.neuropharm.2025.110383","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110383","url":null,"abstract":"<p><p>Depression is a globally prevalent emotional disorder with a complex pathophysiology. Microglia are resident immune cells in the central nervous system, playing crucial roles in regulating inflammation, synaptic plasticity, immune phagocytosis, and other functions, thereby exerting significant impacts on neuropsychiatric disorders like depression. Increasing research indicates that abnormal phagocytic function of microglia in the brain is involved in depression, showing excessive or insufficient phagocytosis in different states. Here, we have provided a review of the signaling molecules involved in microglial phagocytosis in depression, including \"eat me\" signals such as phosphatidylserine (PS), complement, and \"don't eat me\" signals such as CD47, CD200 and related receptors. Furthermore, we discuss the regulatory effects of existing pharmaceuticals and dietary nutrients on microglial phagocytosis in depression, emphasizing the need for tailored modulation based on the varying phagocytic states of microglia. This review aims to facilitate a deeper understanding of the role of microglial phagocytosis in depression and provide a roadmap for potential therapeutic strategies for depression targeting microglial phagocytosis.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110383"},"PeriodicalIF":4.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-21DOI: 10.1016/j.neuropharm.2025.110382
Ana Oliveira, Márcia Azevedo, Rafaela Seixas, Soraia Silva, Raquel Martinho, Paula Serrão, Elisabete Silva, Mónica Moreira-Rodrigues
Adrenaline (Ad) strengthens contextual fear memory by increasing blood glucose, possibly enhancing hippocampus acetylcholine synthesis. Nevertheless, it is unclear if peripheral Ad influences the cholinergic system, contributing to contextual fear memory strengthening. We aimed to evaluate whether peripheral Ad alters muscarinic receptor expression and if the cholinergic system is involved in peripheral Ad contextual fear memory strengthening effect. Wild-type (WT) and Ad-deficient male mice (129x1/SvJ) underwent a fear conditioning procedure followed by intraperitoneal pre-training and pre-context administration of Ad (0.1 mg/kg), atropine (10 mg/kg), methylatropine (0.5 mg/kg), Ad (0.1 mg/kg) plus atropine (10 mg/kg) or vehicle (NaCl, 0.9%). Shock responsiveness and freezing behaviour were accessed. Hippocampal M1, M2, and M4 mRNA expression were evaluated. Ad-deficient mice presented decreased hippocampal muscarinic M4 subtype receptor mRNA expression compared to WT mice. In Ad-administered Ad-deficient mice, hippocampal muscarinic M4 subtype receptor mRNA expression increased compared with vehicle-administered Ad-deficient mice. On the context day, atropine-administered WT mice presented decreased freezing behaviour compared to vehicle or methylatropine-administered WT mice. Moreover, Ad plus atropine-administered Ad-deficient mice led to decreased freezing behaviour compared to Ad-administered Ad-deficient mice. In conclusion, Ad-deficient mice`s contextual fear memory impairment was associated with hippocampal muscarinic M4 subtype receptor down expression, which was reversed by Ad. This may be related to contextual fear memory consolidation or retrieval induced by peripheral Ad. Furthermore, the effect of Ad contextual fear memory might be due to increased hippocampus muscarinic subtype M4 expression, which may contribute to increased cholinergic activity in the central nervous system.
{"title":"Hippocampus muscarinic M4 receptor mRNA expression may influence central cholinergic activity, causing fear memory strengthening by peripheral adrenaline.","authors":"Ana Oliveira, Márcia Azevedo, Rafaela Seixas, Soraia Silva, Raquel Martinho, Paula Serrão, Elisabete Silva, Mónica Moreira-Rodrigues","doi":"10.1016/j.neuropharm.2025.110382","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110382","url":null,"abstract":"<p><p>Adrenaline (Ad) strengthens contextual fear memory by increasing blood glucose, possibly enhancing hippocampus acetylcholine synthesis. Nevertheless, it is unclear if peripheral Ad influences the cholinergic system, contributing to contextual fear memory strengthening. We aimed to evaluate whether peripheral Ad alters muscarinic receptor expression and if the cholinergic system is involved in peripheral Ad contextual fear memory strengthening effect. Wild-type (WT) and Ad-deficient male mice (129x1/SvJ) underwent a fear conditioning procedure followed by intraperitoneal pre-training and pre-context administration of Ad (0.1 mg/kg), atropine (10 mg/kg), methylatropine (0.5 mg/kg), Ad (0.1 mg/kg) plus atropine (10 mg/kg) or vehicle (NaCl, 0.9%). Shock responsiveness and freezing behaviour were accessed. Hippocampal M<sub>1</sub>, M<sub>2</sub>, and M<sub>4</sub> mRNA expression were evaluated. Ad-deficient mice presented decreased hippocampal muscarinic M<sub>4</sub> subtype receptor mRNA expression compared to WT mice. In Ad-administered Ad-deficient mice, hippocampal muscarinic M<sub>4</sub> subtype receptor mRNA expression increased compared with vehicle-administered Ad-deficient mice. On the context day, atropine-administered WT mice presented decreased freezing behaviour compared to vehicle or methylatropine-administered WT mice. Moreover, Ad plus atropine-administered Ad-deficient mice led to decreased freezing behaviour compared to Ad-administered Ad-deficient mice. In conclusion, Ad-deficient mice`s contextual fear memory impairment was associated with hippocampal muscarinic M<sub>4</sub> subtype receptor down expression, which was reversed by Ad. This may be related to contextual fear memory consolidation or retrieval induced by peripheral Ad. Furthermore, the effect of Ad contextual fear memory might be due to increased hippocampus muscarinic subtype M<sub>4</sub> expression, which may contribute to increased cholinergic activity in the central nervous system.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110382"},"PeriodicalIF":4.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-21DOI: 10.1016/j.neuropharm.2025.110370
Samantha G Malone, Navid S Tavakoli, Peggy S Keller, Michael T Bardo, Pavel I Ortinski
The central amygdala (CeA) is involved in opioid relapse-associated behaviors. This study determined if escalation of fentanyl intake as modeled by long-access (LgA) self-administration (SA) alters ex vivo neuronal activity in CeA in response to fentanyl during acute withdrawal and protracted abstinence. Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl or saline across 7 daily 1-h short access (ShA) sessions, followed by 21 6-h long access (LgA) sessions. Following acute (17 h) or protracted (30 days) withdrawal, withdrawal signs were assessed and rats were euthanized for CeA calcium imaging in brain slices. Fentanyl rats demonstrated reduced basal frequency of activity after 30 days withdrawal, but not after 17 h withdrawal. Regardless of SA group, acute fentanyl application in slices reduced activity (frequency, duration, active cell number) of CeA neurons. In acute withdrawal, the magnitude to which acute fentanyl suppressed CeA neuronal activity was smaller in fentanyl SA rats, relative to saline SA controls. However, the magnitude of acute fentanyl effect on suppression of CeA activity was greater in fentanyl SA rats (vs. saline SA controls) after protracted abstinence.
{"title":"Calcium Imaging of Central Amygdala Activity After Escalation of Fentanyl Self-Administration.","authors":"Samantha G Malone, Navid S Tavakoli, Peggy S Keller, Michael T Bardo, Pavel I Ortinski","doi":"10.1016/j.neuropharm.2025.110370","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2025.110370","url":null,"abstract":"<p><p>The central amygdala (CeA) is involved in opioid relapse-associated behaviors. This study determined if escalation of fentanyl intake as modeled by long-access (LgA) self-administration (SA) alters ex vivo neuronal activity in CeA in response to fentanyl during acute withdrawal and protracted abstinence. Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl or saline across 7 daily 1-h short access (ShA) sessions, followed by 21 6-h long access (LgA) sessions. Following acute (17 h) or protracted (30 days) withdrawal, withdrawal signs were assessed and rats were euthanized for CeA calcium imaging in brain slices. Fentanyl rats demonstrated reduced basal frequency of activity after 30 days withdrawal, but not after 17 h withdrawal. Regardless of SA group, acute fentanyl application in slices reduced activity (frequency, duration, active cell number) of CeA neurons. In acute withdrawal, the magnitude to which acute fentanyl suppressed CeA neuronal activity was smaller in fentanyl SA rats, relative to saline SA controls. However, the magnitude of acute fentanyl effect on suppression of CeA activity was greater in fentanyl SA rats (vs. saline SA controls) after protracted abstinence.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110370"},"PeriodicalIF":4.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1016/j.neuropharm.2025.110374
Qi Li , Yiwei Huang , Tao Ban , Kexin Chen , Xuechu Zhen , Qijun Dai , Gufang Zhang
Serum amyloid A (SAA) is an acute-phase protein that has been recognized as a diagnostic biomarker for several diseases. However, the functional studies about the effects of SAA on microglial activation seem controversial. Here, we discovered that SAA induces microglial cells polarize to a pro-resolving M2 phenotype by promoting the stability of the transcription factor Nrf2, which specifically regulates microglia towards a pro-resolving phenotype via metabolic reprogramming. Moreover, we identified that the AMPK/mTOR signaling pathway is involved in SAA-induced Nrf2 upregulation. Additionally, SAA protects cultured neuronal cells from MPP+-induced damage, and furthermore, local administration of SAA into the substantia nigra significantly attenuated MPTP-induced dopaminergic neuronal loss, thereby improving motor impairments in mice. In conclusion, for the first time we demonstrate SAA regulate microglial activation by promoting Nrf2 stabilization, ultimately protecting dopaminergic neurons and alleviating MPTP-induced PD-like pathology.
{"title":"Serum amyloid A drive microglia shift to a resolving phenotype through Nrf2","authors":"Qi Li , Yiwei Huang , Tao Ban , Kexin Chen , Xuechu Zhen , Qijun Dai , Gufang Zhang","doi":"10.1016/j.neuropharm.2025.110374","DOIUrl":"10.1016/j.neuropharm.2025.110374","url":null,"abstract":"<div><div>Serum amyloid A (SAA) is an acute-phase protein that has been recognized as a diagnostic biomarker for several diseases. However, the functional studies about the effects of SAA on microglial activation seem controversial. Here, we discovered that SAA induces microglial cells polarize to a pro-resolving M2 phenotype by promoting the stability of the transcription factor Nrf2, which specifically regulates microglia towards a pro-resolving phenotype via metabolic reprogramming. Moreover, we identified that the AMPK/mTOR signaling pathway is involved in SAA-induced Nrf2 upregulation. Additionally, SAA protects cultured neuronal cells from MPP<sup>+</sup>-induced damage, and furthermore, local administration of SAA into the substantia nigra significantly attenuated MPTP-induced dopaminergic neuronal loss, thereby improving motor impairments in mice. In conclusion, for the first time we demonstrate SAA regulate microglial activation by promoting Nrf2 stabilization, ultimately protecting dopaminergic neurons and alleviating MPTP-induced PD-like pathology.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110374"},"PeriodicalIF":4.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1016/j.neuropharm.2025.110371
Shivani P. Vaidya , Roberta G. Anversa , Paulo Pinares-Garcia , Leigh C. Walker , Natasha Pracejus , Christopher A. Reid , Andrew J. Lawrence
Globally, around 400 million people live with an alcohol use disorder (AUD), yet current treatments available are suboptimal at a population level. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in the modulation of complex motivated behaviours, including reward seeking. Here, we investigated the potential involvement of HCN channels in alcohol reinforcing effects, contributing to alcohol intake and relapse-like drinking following abstinence in iP rats. The functional role of HCN channels in the motivation to acquire alcohol and relapse-like behaviour was tested in vivo through intracerebroventricular (ICV) infusion of a HCN channel inhibitor, ZD7288 prior to operant progressive ratio responding or the alcohol deprivation effect. Acute ICV infusion of ZD7288 (3 μg/5 μL) significantly reduced motivation to acquire alcohol and attenuated the alcohol deprivation effect after 14 days of abstinence, without affecting spontaneous locomotor activity. HCN channels are densely expressed in cholinergic neurons of the medial habenula (mHb), which have been implicated in stress, aversion, and drug/alcohol intake-associated behaviours. To investigate the impact of alcohol on the expression of HCN channels, cholinergic markers and acetylcholine receptors, we performed qPCR on mHb tissue in alcohol-preferring (iP) rats following chronic voluntary alcohol intake or abstinence. qPCR results showed an upregulation of mRNA encoding key ion channels in the mHb following abstinence from chronic voluntary alcohol use. Collectively, these findings suggest that HCN channels contribute to motivation to consume alcohol and relapse-like behaviour during abstinence in iP rats.
{"title":"Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats","authors":"Shivani P. Vaidya , Roberta G. Anversa , Paulo Pinares-Garcia , Leigh C. Walker , Natasha Pracejus , Christopher A. Reid , Andrew J. Lawrence","doi":"10.1016/j.neuropharm.2025.110371","DOIUrl":"10.1016/j.neuropharm.2025.110371","url":null,"abstract":"<div><div>Globally, around 400 million people live with an alcohol use disorder (AUD), yet current treatments available are suboptimal at a population level. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in the modulation of complex motivated behaviours, including reward seeking. Here, we investigated the potential involvement of HCN channels in alcohol reinforcing effects, contributing to alcohol intake and relapse-like drinking following abstinence in iP rats. The functional role of HCN channels in the motivation to acquire alcohol and relapse-like behaviour was tested <em>in vivo</em> through intracerebroventricular (ICV) infusion of a HCN channel inhibitor, ZD7288 prior to operant progressive ratio responding or the alcohol deprivation effect. Acute ICV infusion of ZD7288 (3 μg/5 μL) significantly reduced motivation to acquire alcohol and attenuated the alcohol deprivation effect after 14 days of abstinence, without affecting spontaneous locomotor activity. HCN channels are densely expressed in cholinergic neurons of the medial habenula (mHb), which have been implicated in stress, aversion, and drug/alcohol intake-associated behaviours. To investigate the impact of alcohol on the expression of HCN channels, cholinergic markers and acetylcholine receptors, we performed qPCR on mHb tissue in alcohol-preferring (iP) rats following chronic voluntary alcohol intake or abstinence. qPCR results showed an upregulation of mRNA encoding key ion channels in the mHb following abstinence from chronic voluntary alcohol use. Collectively, these findings suggest that HCN channels contribute to motivation to consume alcohol and relapse-like behaviour during abstinence in iP rats.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110371"},"PeriodicalIF":4.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Visceral hypersensitivity is one of the most prevalent symptoms of inflammatory bowel disease (IBD), and it can be difficult to cure despite achieving endoscopic remission. Accumulating studies have described that macrophage colony-stimulating factor (M-CSF) modulates neuroinflammation in the central nervous system (CNS) and the development of chronic pain, while the underlying mechanism for whether and how M-CSF/CSF1R signaling pathway regulates visceral hypersensitivity following colitis remains unknown. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we determined that microglial accumulation occurred in the spinal dorsal horn during remission phase. The reactive microglia released inflammatory factor, increased neuronal excitability in the dorsal horn, and produced chronic visceral pain behaviors in DSS-treated adult male mice. In addition, we also found significantly increased signaling mediated by astrocytic M-CSF and microglial CSF1R in dorsal horn in the mice with colitis. Exogenous M-CSF induced microglial activation, neuronal hyperactivity and behavioral hypersensitivity in the control group, inhibition of astrocyte/microglia by fluorocitrate/minocycline significantly suppressed microglial and neuronal activity, and relieved the visceral hypersensitivity in the model mice. Overall, our experimental study uncovers the critical involvement of spinal astrocyte-derived M-CSF and reactive microglia in the initiation and maintenance of visceral hypersensitivity following colitis, thereby identifying spinal M-CSF as a target for treating chronic visceral pain. This may provide more accurate theoretical guidance for clinical patients with IBD.
{"title":"Spinal astrocyte-derived M-CSF mediates microglial reaction and drives visceral hypersensitivity following DSS-induced colitis","authors":"Ke Wu , Shuai Shao , Yu-ting Dong , Yue-ying Liu , Xing-han Chen , Peng Cheng , Xia Qin , Xiao-han Peng , Yong-mei Zhang","doi":"10.1016/j.neuropharm.2025.110373","DOIUrl":"10.1016/j.neuropharm.2025.110373","url":null,"abstract":"<div><div>Visceral hypersensitivity is one of the most prevalent symptoms of inflammatory bowel disease (IBD), and it can be difficult to cure despite achieving endoscopic remission. Accumulating studies have described that macrophage colony-stimulating factor (M-CSF) modulates neuroinflammation in the central nervous system (CNS) and the development of chronic pain, while the underlying mechanism for whether and how M-CSF/CSF1R signaling pathway regulates visceral hypersensitivity following colitis remains unknown. In the present study, using the dextran sulfate sodium (DSS)-induced colitis model, we determined that microglial accumulation occurred in the spinal dorsal horn during remission phase. The reactive microglia released inflammatory factor, increased neuronal excitability in the dorsal horn, and produced chronic visceral pain behaviors in DSS-treated adult male mice. In addition, we also found significantly increased signaling mediated by astrocytic M-CSF and microglial CSF1R in dorsal horn in the mice with colitis. Exogenous M-CSF induced microglial activation, neuronal hyperactivity and behavioral hypersensitivity in the control group, inhibition of astrocyte/microglia by fluorocitrate/minocycline significantly suppressed microglial and neuronal activity, and relieved the visceral hypersensitivity in the model mice. Overall, our experimental study uncovers the critical involvement of spinal astrocyte-derived M-CSF and reactive microglia in the initiation and maintenance of visceral hypersensitivity following colitis, thereby identifying spinal M-CSF as a target for treating chronic visceral pain. This may provide more accurate theoretical guidance for clinical patients with IBD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110373"},"PeriodicalIF":4.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-17DOI: 10.1016/j.neuropharm.2025.110372
Christopher T. Searles , Meghan E. Vogt , Iyanuoluwa Adedokun, Anne Z. Murphy
It is currently estimated that every 15 minutes an infant is born with opioid use disorder and undergoes intense early life trauma due to opioid withdrawal. Clinical research on the long-term consequences of gestational opioid exposure reports increased rates of social, conduct, and emotional disorders in these children. Here, we investigate the impact of perinatal opioid exposure (POE) on behaviors associated with anhedonia and stress in male and female Sprague Dawley rats. Young adult female rats were administered morphine via programmable, subcutaneous micro-infusion pumps before, during, and through one week post gestation. For the first two postnatal weeks, maternal behavior was examined for fragmentation and unpredictability. Unpredictable behavioral patterns were quantitatively characterized as entropy scores. Offspring were assessed for sucrose preference, social behavior, and stress responsivity. Overall, dams that received morphine across gestation displayed significantly less pup-directed behavior with increased fragmentation for nursing and higher entropy scores. In adolescence, male and female rat offspring exposed to morphine displayed reduced sucrose preference and, as adults, spent significantly less time interacting with familiar conspecifics. Changes in social behaviors were linked to increased activity in nondopaminergic cells of mesolimbic reward brain regions. Although no treatment effects were observed in forced swim test performance, corticosterone levels were significantly increased in POE adult males. Together, these results suggest that perinatal morphine exposure promotes anhedonic behavior, possibly due to fragmented and unpredictable maternal behavior in opioid-dependent dams.
{"title":"Disrupted maternal behavior in morphine-dependent pregnant rats and anhedonia in their offspring","authors":"Christopher T. Searles , Meghan E. Vogt , Iyanuoluwa Adedokun, Anne Z. Murphy","doi":"10.1016/j.neuropharm.2025.110372","DOIUrl":"10.1016/j.neuropharm.2025.110372","url":null,"abstract":"<div><div>It is currently estimated that every 15 minutes an infant is born with opioid use disorder and undergoes intense early life trauma due to opioid withdrawal. Clinical research on the long-term consequences of gestational opioid exposure reports increased rates of social, conduct, and emotional disorders in these children. Here, we investigate the impact of perinatal opioid exposure (POE) on behaviors associated with anhedonia and stress in male and female Sprague Dawley rats. Young adult female rats were administered morphine via programmable, subcutaneous micro-infusion pumps before, during, and through one week post gestation. For the first two postnatal weeks, maternal behavior was examined for fragmentation and unpredictability. Unpredictable behavioral patterns were quantitatively characterized as entropy scores. Offspring were assessed for sucrose preference, social behavior, and stress responsivity. Overall, dams that received morphine across gestation displayed significantly less pup-directed behavior with increased fragmentation for nursing and higher entropy scores. In adolescence, male and female rat offspring exposed to morphine displayed reduced sucrose preference and, as adults, spent significantly less time interacting with familiar conspecifics. Changes in social behaviors were linked to increased activity in nondopaminergic cells of mesolimbic reward brain regions. Although no treatment effects were observed in forced swim test performance, corticosterone levels were significantly increased in POE adult males. Together, these results suggest that perinatal morphine exposure promotes anhedonic behavior, possibly due to fragmented and unpredictable maternal behavior in opioid-dependent dams.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110372"},"PeriodicalIF":4.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cannabis abuse has increased with the continuous relaxation of cannabis policies. However, the mechanism by which Δ9-tetrahydrocannabinol (THC) negatively affects the central nervous system, especially the blood-brain barrier (BBB), remains unclear. THC exposure models were established in vivo and in vitro. The BBB properties were examined using Western blotting (WB), immunofluorescence staining (IF), transendothelial electrical resistance (TEER), and flux of sodium fluorescein (SF). The oxidative stress regulators were examined using IF and assay kits. The activation of cannabinoid receptor 1 (CB1R) was examined using WB and IF. The THC exposure caused barrier integrity damage and endothelial dysfunction in murine and hCMEC/D3 cells, conclude albumin leakage, increased SF permeability and reduced TEER value. The expression of tight junction proteins, including claudin 5, occludin, and junctional adhesion molecules, was decreased. Additionally, key oxidative stress regulators, including reactive oxygen species, hydrogen peroxide, malonaldehyde levels, and antioxidant enzyme activities, including catalase, glutathione peroxidase, glutathione S-transferase, and superoxide dismutase, and heme oxygenase 1, were increased. Activation of CB1R has been detected in brain microvascular endothelial cells in vivo and in vitro. Furthermore, inhibition of oxidative stress and CB1R could mitigate the aforementioned conditions and BBB damage after THC exposure. The effect of THC on murine and human brain microvascular endothelial cells revealed that THC-induced BBB damage was partly mediated by CB1R activation, triggering the oxidative stress response. This study provides new theoretical insights into the mechanisms of THC-induced BBB damage and offers novel scientific evidence for the potential neurotoxicity and adverse reactions induced by THC.
{"title":"Δ9-tetrahydrocannabinol induces blood-brain barrier disruption: Involving the activation of CB1R and oxidative stress","authors":"Qianyao Zhang, Wenxin Huang, Taokun Li, Xuemei Wang, Ximin Lai, Wei Hu, Zhihong Li, Xiaofeng Zeng, Jian Huang, Ruilin Zhang","doi":"10.1016/j.neuropharm.2025.110366","DOIUrl":"10.1016/j.neuropharm.2025.110366","url":null,"abstract":"<div><div>Cannabis abuse has increased with the continuous relaxation of cannabis policies. However, the mechanism by which Δ<sup>9</sup>-tetrahydrocannabinol (THC) negatively affects the central nervous system, especially the blood-brain barrier (BBB), remains unclear. THC exposure models were established <em>in vivo</em> and <em>in vitro</em>. The BBB properties were examined using Western blotting (WB), immunofluorescence staining (IF), transendothelial electrical resistance (TEER), and flux of sodium fluorescein (SF). The oxidative stress regulators were examined using IF and assay kits. The activation of cannabinoid receptor 1 (CB1R) was examined using WB and IF. The THC exposure caused barrier integrity damage and endothelial dysfunction in murine and hCMEC/D<sub>3</sub> cells, conclude albumin leakage, increased SF permeability and reduced TEER value. The expression of tight junction proteins, including claudin 5, occludin, and junctional adhesion molecules, was decreased. Additionally, key oxidative stress regulators, including reactive oxygen species, hydrogen peroxide, malonaldehyde levels, and antioxidant enzyme activities, including catalase, glutathione peroxidase, glutathione S-transferase, and superoxide dismutase, and heme oxygenase 1, were increased. Activation of CB1R has been detected in brain microvascular endothelial cells <em>in vivo</em> and <em>in vitro</em>. Furthermore, inhibition of oxidative stress and CB1R could mitigate the aforementioned conditions and BBB damage after THC exposure. The effect of THC on murine and human brain microvascular endothelial cells revealed that THC-induced BBB damage was partly mediated by CB1R activation, triggering the oxidative stress response. This study provides new theoretical insights into the mechanisms of THC-induced BBB damage and offers novel scientific evidence for the potential neurotoxicity and adverse reactions induced by THC.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110366"},"PeriodicalIF":4.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-15DOI: 10.1016/j.neuropharm.2025.110367
Sivakumar Srinivasan , Fabian Limani , Michaela Hanzlova , Ségolène La Batide-Alanore , Sigrid Klotz , Thomas S. Hnasko , Thomas Steinkellner
Midbrain dopamine (DA) neurons comprise a heterogeneous population of cells. For instance, some DA neurons express the vesicular glutamate transporter VGLUT2 allowing these cells to co-release DA and glutamate. Additionally, GABA may be co-released from DA neurons. However, most cells do not express the canonical machinery to synthesize GABA or the vesicular GABA transporter VGAT. Instead, GABA seems to be taken up into DA neurons by a plasmalemmal GABA transporter (GAT1) and stored in synaptic vesicles via the vesicular monoamine transporter VMAT2. Yet, it remains unclear whether GABA indeed interacts with VMAT2.
Here, we used radiotracer flux measurements in VMAT2 expressing HEK-293 cells and synaptic vesicles from male and female mice to determine whether GABA qualifies as substrate at VMAT2. We found that GABA reduced uptake of VMAT2 substrates in mouse synaptic vesicle preparations from striatum and cerebellum at millimolar concentrations but had no effect in VMAT2-expressing HEK-293 cells. Interestingly, while the closely related amino acid glycine did not affect substrate uptake at VMAT2 in mouse synaptic vesicles, the amino sulfonic acid taurine reduced uptake similar to GABA. Lastly, we discovered that the majority of mouse and human midbrain DA neurons in the substantia nigra of either sex expressed VMAT2 and GAT1 suggesting that most of them could be capable of co-releasing DA and GABA. Together, our findings suggest that GABA is a low-affinity substrate at VMAT2 with potential implications for basal ganglia physiology and disease.
{"title":"Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2 – Implications for transmitter co-release from dopamine neurons","authors":"Sivakumar Srinivasan , Fabian Limani , Michaela Hanzlova , Ségolène La Batide-Alanore , Sigrid Klotz , Thomas S. Hnasko , Thomas Steinkellner","doi":"10.1016/j.neuropharm.2025.110367","DOIUrl":"10.1016/j.neuropharm.2025.110367","url":null,"abstract":"<div><div>Midbrain dopamine (DA) neurons comprise a heterogeneous population of cells. For instance, some DA neurons express the vesicular glutamate transporter VGLUT2 allowing these cells to co-release DA and glutamate. Additionally, GABA may be co-released from DA neurons. However, most cells do not express the canonical machinery to synthesize GABA or the vesicular GABA transporter VGAT. Instead, GABA seems to be taken up into DA neurons by a plasmalemmal GABA transporter (GAT1) and stored in synaptic vesicles via the vesicular monoamine transporter VMAT2. Yet, it remains unclear whether GABA indeed interacts with VMAT2.</div><div>Here, we used radiotracer flux measurements in VMAT2 expressing HEK-293 cells and synaptic vesicles from male and female mice to determine whether GABA qualifies as substrate at VMAT2. We found that GABA reduced uptake of VMAT2 substrates in mouse synaptic vesicle preparations from striatum and cerebellum at millimolar concentrations but had no effect in VMAT2-expressing HEK-293 cells. Interestingly, while the closely related amino acid glycine did not affect substrate uptake at VMAT2 in mouse synaptic vesicles, the amino sulfonic acid taurine reduced uptake similar to GABA. Lastly, we discovered that the majority of mouse and human midbrain DA neurons in the substantia nigra of either sex expressed VMAT2 and GAT1 suggesting that most of them could be capable of co-releasing DA and GABA. Together, our findings suggest that GABA is a low-affinity substrate at VMAT2 with potential implications for basal ganglia physiology and disease.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110367"},"PeriodicalIF":4.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-14DOI: 10.1016/j.neuropharm.2025.110368
Henriette Nyberg , Inger Lise Bogen , Nur Duale , Jannike Mørch Andersen
While the use of methadone or buprenorphine during pregnancy is beneficial for the mother's health compared to illicit opioid use, prenatal exposure to these medications may have adverse consequences for the unborn child. However, the underlying molecular mechanisms of prenatal opioid exposure on neurodevelopment remain poorly understood. Hence, this study aimed to investigate gene expression changes, focusing on synapse-related genes, in cerebral tissue from newborn rats prenatally exposed to methadone or buprenorphine. Female Sprague-Dawley rats were exposed to methadone (10 mg/kg/day), buprenorphine (1 mg/kg/day), or sterile water through osmotic minipumps during pregnancy. Total RNA was isolated from the cerebrum on postnatal day 2 and analyzed using RNA-sequencing. Analyses of differentially expressed genes (DEGs) and enriched biological processes were conducted to compare the gene expression profiles between treatment groups within each sex. Prenatal buprenorphine exposure resulted in 598 DEGs (333 up- and 265 downregulated) in males and 175 (75 up- and 100 downregulated) in females, while prenatal methadone exposure resulted in 335 DEGs (224 up- and 111 downregulated) in males and 201 (57 up- and 144 downregulated) in females. Gene ontology analyses demonstrated that enriched biological processes included synaptic signaling, immune responses, and apoptosis. Analysis of the DEGs using the synapse database SynGO revealed that males prenatally exposed to buprenorphine displayed the highest number of enriched synapse-related biological process terms. Understanding gene expression changes following prenatal methadone or buprenorphine exposure is crucial to uncover the mechanisms underlying behavioral alterations and to develop interventions to mitigate the impact of opioid exposure on neurodevelopment.
{"title":"Prenatal exposure to methadone or buprenorphine alters transcriptional networks associated with synaptic signaling in newborn rats","authors":"Henriette Nyberg , Inger Lise Bogen , Nur Duale , Jannike Mørch Andersen","doi":"10.1016/j.neuropharm.2025.110368","DOIUrl":"10.1016/j.neuropharm.2025.110368","url":null,"abstract":"<div><div>While the use of methadone or buprenorphine during pregnancy is beneficial for the mother's health compared to illicit opioid use, prenatal exposure to these medications may have adverse consequences for the unborn child. However, the underlying molecular mechanisms of prenatal opioid exposure on neurodevelopment remain poorly understood. Hence, this study aimed to investigate gene expression changes, focusing on synapse-related genes, in cerebral tissue from newborn rats prenatally exposed to methadone or buprenorphine. Female Sprague-Dawley rats were exposed to methadone (10 mg/kg/day), buprenorphine (1 mg/kg/day), or sterile water through osmotic minipumps during pregnancy. Total RNA was isolated from the cerebrum on postnatal day 2 and analyzed using RNA-sequencing. Analyses of differentially expressed genes (DEGs) and enriched biological processes were conducted to compare the gene expression profiles between treatment groups within each sex. Prenatal buprenorphine exposure resulted in 598 DEGs (333 up- and 265 downregulated) in males and 175 (75 up- and 100 downregulated) in females, while prenatal methadone exposure resulted in 335 DEGs (224 up- and 111 downregulated) in males and 201 (57 up- and 144 downregulated) in females. Gene ontology analyses demonstrated that enriched biological processes included synaptic signaling, immune responses, and apoptosis. Analysis of the DEGs using the synapse database SynGO revealed that males prenatally exposed to buprenorphine displayed the highest number of enriched synapse-related biological process terms. Understanding gene expression changes following prenatal methadone or buprenorphine exposure is crucial to uncover the mechanisms underlying behavioral alterations and to develop interventions to mitigate the impact of opioid exposure on neurodevelopment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110368"},"PeriodicalIF":4.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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