Pub Date : 2026-02-01Epub Date: 2025-10-26DOI: 10.1016/j.neuropharm.2025.110745
Christian P. Müller , Bernd Lenz , Johannes Kornhuber , Ulrich W. Ebner-Priemer , Emanuel Schwarz , Karen D. Ersche , Falk Kiefer , Rainer Spanagel
Alcohol use disorder (AUD) is a prevalent psychiatric disorder that continually causes significant suffering. Although pharmacotherapies are available, they have low efficacy and show little compliance. Thus, new approaches for AUD treatment are still needed. The core symptoms of AUD include drug seeking, consumption, and withdrawal, which occur in distinct shifted time phases. Recent neurobiological research has revealed that these phases have rather unique underlying neurobiological processes and neuropharmacology. We propose a new treatment strategy based on available pharmacotherapies with small effects on individual AUD phases and independent advancements in diagnosis tool technology. The strategy combines a pharmacological toolbox with an ecological momentary assessment (EMA) tool. An artificial intelligence-coupled EMA device is provided to patients and can act as a near real-time diagnostic monitor, a phase-sensitive individualized treatment guide, and a metric for therapeutic success. The EMA tool will allow highly individual AUD phases to be targeted with tailored neuropharmacology in near real time. This approach may revolutionize the pharmacotherapies used for mental disorders.
{"title":"Phase-sensitive individualized pharmacotherapy for alcohol use disorder","authors":"Christian P. Müller , Bernd Lenz , Johannes Kornhuber , Ulrich W. Ebner-Priemer , Emanuel Schwarz , Karen D. Ersche , Falk Kiefer , Rainer Spanagel","doi":"10.1016/j.neuropharm.2025.110745","DOIUrl":"10.1016/j.neuropharm.2025.110745","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) is a prevalent psychiatric disorder that continually causes significant suffering. Although pharmacotherapies are available, they have low efficacy and show little compliance. Thus, new approaches for AUD treatment are still needed. The core symptoms of AUD include drug seeking, consumption, and withdrawal, which occur in distinct shifted time phases. Recent neurobiological research has revealed that these phases have rather unique underlying neurobiological processes and neuropharmacology. We propose a new treatment strategy based on available pharmacotherapies with small effects on individual AUD phases and independent advancements in diagnosis tool technology. The strategy combines a pharmacological toolbox with an ecological momentary assessment (EMA) tool. An artificial intelligence-coupled EMA device is provided to patients and can act as a near real-time diagnostic monitor, a phase-sensitive individualized treatment guide, and a metric for therapeutic success. The EMA tool will allow highly individual AUD phases to be targeted with tailored neuropharmacology in near real time. This approach may revolutionize the pharmacotherapies used for mental disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110745"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391700","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 : 2026-02-01Epub Date: 2025-10-28DOI: 10.1016/j.neuropharm.2025.110753
Ammar Al-Omari , Péter Poszovácz , Gergely Berta , Tünde Biró-Sütő , Erika Pintér , Balázs Gaszner , Viktória Kormos
The urocortin 1 (UCN1)-expressing neurons of the centrally projecting Edinger-Westphal nucleus (EWcp) regulate the function of migraine-related brain areas via direct urocortinergic connections. In the central nervous system, EWcp/UCN1 neurons uniquely co-expresses transient receptor potential ankyrin 1 (TRPA1) cation channel, which has also been linked to migraine. Here we aimed to investigate whether central TRPA1 receptors regulate the EWcp/UCN1 neurons’ response to migraine.
The intraperitoneal calcitonin gene related peptide (CGRP) injection model of migraine was implemented and validated using light-dark box and von Frey assays in wild-type (WT) and TRPA1 knockout (KO) male mice. RNAscope in situ hybridization and immunofluorescence were used to examine the Ucn1, Trpa1 mRNA expression and UCN1 peptide content in the EWcp. FOS immunohistochemistry was performed to assess acute neuronal activation in the EWcp and the antinociceptive lateral periaqueductal gray matter (lPAG).
CGRP administration induced light aversion, periorbital hyperalgesia and increased FOS immunoreactivity in the lPAG in both genotypes supporting the model validity. Additionally, Trpa1 deficient mice exhibited reduced sensitivity to light, regardless of the treatment conditions. In the EWcp, CGRP treatment increased FOS immunosignal and Ucn1 mRNA expression in both genotypes. Moreover, in WT mice, the treatment increased the EWcp UCN1 peptide and Trpa1 mRNA levels, with no such changes observed in Trpa1 KO animals. These findings suggest a possible role of central TRPA1 in migraine by regulating UCN1 dynamics in the EWcp. Targeting TRPA1 ion channels through pharmacological interventions may offer a new strategy for migraine treatment.
{"title":"TRPA1 modulates urocortin 1 turnover in the centrally projecting Edinger-Westphal nucleus in a CGRP-induced migraine model","authors":"Ammar Al-Omari , Péter Poszovácz , Gergely Berta , Tünde Biró-Sütő , Erika Pintér , Balázs Gaszner , Viktória Kormos","doi":"10.1016/j.neuropharm.2025.110753","DOIUrl":"10.1016/j.neuropharm.2025.110753","url":null,"abstract":"<div><div>The urocortin 1 (UCN1)-expressing neurons of the centrally projecting Edinger-Westphal nucleus (EWcp) regulate the function of migraine-related brain areas <em>via</em> direct urocortinergic connections. In the central nervous system, EWcp/UCN1 neurons uniquely co-expresses transient receptor potential ankyrin 1 (TRPA1) cation channel, which has also been linked to migraine. Here we aimed to investigate whether central TRPA1 receptors regulate the EWcp/UCN1 neurons’ response to migraine.</div><div>The intraperitoneal calcitonin gene related peptide (CGRP) injection model of migraine was implemented and validated using light-dark box and von Frey assays in wild-type (WT) and TRPA1 knockout (KO) male mice. RNAscope <em>in situ</em> hybridization and immunofluorescence were used to examine the <em>Ucn1</em>, <em>Trpa1</em> mRNA expression and UCN1 peptide content in the EWcp. FOS immunohistochemistry was performed to assess acute neuronal activation in the EWcp and the antinociceptive lateral periaqueductal gray matter (lPAG).</div><div>CGRP administration induced light aversion, periorbital hyperalgesia and increased FOS immunoreactivity in the lPAG in both genotypes supporting the model validity. Additionally, <em>Trpa1</em> deficient mice exhibited reduced sensitivity to light, regardless of the treatment conditions. In the EWcp, CGRP treatment increased FOS immunosignal and <em>Ucn1</em> mRNA expression in both genotypes. Moreover, in WT mice, the treatment increased the EWcp UCN1 peptide and <em>Trpa1</em> mRNA levels, with no such changes observed in <em>Trpa1</em> KO animals. These findings suggest a possible role of central TRPA1 in migraine by regulating UCN1 dynamics in the EWcp. Targeting TRPA1 ion channels through pharmacological interventions may offer a new strategy for migraine treatment.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110753"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409154","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 : 2026-02-01Epub Date: 2025-10-30DOI: 10.1016/j.neuropharm.2025.110749
Alvaro Henrique Bernardo de Lima Silva, Pedro Henrique Azevedo de Oliveira, Joice Maria da Cunha, Janaina Menezes Zanoveli, Bruno Jacson Martynhak
Social support (SS) provided by conspecifics during an aversive situation can influence the processing of fear and anxiety responses. However, the effect of social support on the aversive response produced by stimulation of the dorsolateral periaqueductal gray matter (dPAG) have not yet been investigated. Therefore, we investigated in male and female rats the effect of chemical stimulation of the dPAG with N-methyl-D-aspartate (NMDA) on the acquisition of conditioned place aversion (CPA) and whether stimulation of dPAG would produce a persistent anxiety-like response, using for that the elevated plus maze (EPM) test. The effects of dPAG stimulation were evaluated in the presence or absence of social support (SS) provided by a non-familial, naïve conspecific. We found that during an aversive conditioning session, dPAG stimulation induced freezing behavior in both male and female rats, which was attenuated by the presence of SS. In the CPA test, dPAG stimulation induced aversion in both sexes, while the SS reversed CPA in males, but not in females. Despite this effect in female rats, SS induced a significant increase in appetitive ultrasonic vocalizations (USVs) and a decrease in aversive USVs, along with reduced anxiety-like behavior in both male and female rats. On the other hand, all these beneficial effects observed on the processing of aversive memory and anxiety-like response were not observed in the animals serving as SS providers, which is an aspect that needs to be better investigated. Our findings provide new insights into the role of the dPAG and social support (SS) in the acquisition of aversive responses and in the associated persistent anxiety-like behavior.
同种个体在厌恶情境下提供的社会支持会影响恐惧和焦虑反应的加工。然而，社会支持对刺激背外侧导水管周围灰质（dPAG）产生的厌恶反应的影响尚未得到研究。为此，我们采用升高+迷宫（EPM）实验，研究了n -甲基- d -天冬氨酸（NMDA）对雄性和雌性大鼠dPAG的化学刺激对条件厌恶（CPA）习得的影响，以及dPAG刺激是否会产生持续的焦虑样反应。在有或没有社会支持（SS）的情况下，对dPAG刺激的效果进行了评估，社会支持（SS）是由一个非家族性的naïve同种个体提供的。我们发现，在厌恶条件反射过程中，dPAG刺激诱导了雄性和雌性大鼠的冻结行为，这种行为被SS的存在所减弱。在CPA测试中，dPAG刺激诱导了雄性和雌性大鼠的厌恶行为，而SS在雄性大鼠中逆转了CPA，但在雌性大鼠中没有。尽管在雌性大鼠中有这种作用，但在雄性和雌性大鼠中，SS诱导了食欲超声发声（usv）的显著增加和厌恶超声发声（usv）的减少，以及焦虑样行为的减少。另一方面，这些对厌恶记忆加工和焦虑样反应的有益影响在作为SS提供者的动物中没有观察到，这是一个需要进一步研究的方面。我们的研究结果为dPAG和社会支持（SS）在厌恶反应的获得和相关的持续焦虑样行为中的作用提供了新的见解。
{"title":"Influence of social support on the acquisition of conditioned place aversion induced by chemical stimulation of the dorsal periaqueductal gray matter: a sex-dependent approach","authors":"Alvaro Henrique Bernardo de Lima Silva, Pedro Henrique Azevedo de Oliveira, Joice Maria da Cunha, Janaina Menezes Zanoveli, Bruno Jacson Martynhak","doi":"10.1016/j.neuropharm.2025.110749","DOIUrl":"10.1016/j.neuropharm.2025.110749","url":null,"abstract":"<div><div>Social support (SS) provided by conspecifics during an aversive situation can influence the processing of fear and anxiety responses. However, the effect of social support on the aversive response produced by stimulation of the dorsolateral periaqueductal gray matter (dPAG) have not yet been investigated. Therefore, we investigated in male and female rats the effect of chemical stimulation of the dPAG with N-methyl-D-aspartate (NMDA) on the acquisition of conditioned place aversion (CPA) and whether stimulation of dPAG would produce a persistent anxiety-like response, using for that the elevated plus maze (EPM) test. The effects of dPAG stimulation were evaluated in the presence or absence of social support (SS) provided by a non-familial, naïve conspecific. We found that during an aversive conditioning session, dPAG stimulation induced freezing behavior in both male and female rats, which was attenuated by the presence of SS. In the CPA test, dPAG stimulation induced aversion in both sexes, while the SS reversed CPA in males, but not in females. Despite this effect in female rats, SS induced a significant increase in appetitive ultrasonic vocalizations (USVs) and a decrease in aversive USVs, along with reduced anxiety-like behavior in both male and female rats. On the other hand, all these beneficial effects observed on the processing of aversive memory and anxiety-like response were not observed in the animals serving as SS providers, which is an aspect that needs to be better investigated. Our findings provide new insights into the role of the dPAG and social support (SS) in the acquisition of aversive responses and in the associated persistent anxiety-like behavior.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110749"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422221","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 : 2026-02-01Epub Date: 2025-10-22DOI: 10.1016/j.neuropharm.2025.110731
Cui-Yuan Chen , Xin-Ran Yang , Meng Wang , Yi Zhang , Shuai Hou , Muhammad Tahir Khan , Da-Neng Wei , Jia-Si Wu , Ya-Fei Zhao
Major depressive disorder (MDD) is a prevalent psychiatric disease, and understanding its neurochemical basis is crucial for developing new treatments. Acute stress models are often used to study behaviors relevant to depression. This study investigated the source and role of extracellular adenosine in the ventral hippocampal CA1 region during acute stress-induced depressive-like behavior. Using fiber photometry with GRAB fluorescent sensors (GRABATP1.0 and GRABAdo1.0) in mice, we monitored real-time dynamics of adenosine and ATP in response to tail suspension test (TST) and foot shock (FS). Both stressors significantly increased extracellular adenosine levels, while only FS elevated ATP. Pharmacological blockade revealed distinct adenosine sources: TST-induced adenosine primarily originated from ENT1/2-mediated transmembrane efflux, whereas FS-derived adenosine involved both ENT1/2 transport and CD73-dependent ATP hydrolysis. Behaviorally, inhibiting both pathways alleviated FS-induced depressive phenotypes, and exogenous ATP/adenosine administration in the CA1 region exacerbated depressive-like behaviors (e.g., increased immobility in TST, reduced exploration). These findings establish that distinct sources of extracellular adenosine in the ventral hippocampal CA1 region contribute to acute stress induced depressive-like behavior. This work improves our understanding of purinergic signaling in stress responses and may inform future research into novel therapeutic strategies for mood disorders.
{"title":"Extracellular adenosine in acute stress-induced depressive-like behavior: Where does it come from?","authors":"Cui-Yuan Chen , Xin-Ran Yang , Meng Wang , Yi Zhang , Shuai Hou , Muhammad Tahir Khan , Da-Neng Wei , Jia-Si Wu , Ya-Fei Zhao","doi":"10.1016/j.neuropharm.2025.110731","DOIUrl":"10.1016/j.neuropharm.2025.110731","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a prevalent psychiatric disease, and understanding its neurochemical basis is crucial for developing new treatments. Acute stress models are often used to study behaviors relevant to depression. This study investigated the source and role of extracellular adenosine in the ventral hippocampal CA1 region during acute stress-induced depressive-like behavior. Using fiber photometry with GRAB fluorescent sensors (GRAB<sub>ATP1.0</sub> and GRAB<sub>Ado1.0</sub>) in mice, we monitored real-time dynamics of adenosine and ATP in response to tail suspension test (TST) and foot shock (FS). Both stressors significantly increased extracellular adenosine levels, while only FS elevated ATP. Pharmacological blockade revealed distinct adenosine sources: TST-induced adenosine primarily originated from ENT1/2-mediated transmembrane efflux, whereas FS-derived adenosine involved both ENT1/2 transport and CD73-dependent ATP hydrolysis. Behaviorally, inhibiting both pathways alleviated FS-induced depressive phenotypes, and exogenous ATP/adenosine administration in the CA1 region exacerbated depressive-like behaviors (e.g., increased immobility in TST, reduced exploration). These findings establish that distinct sources of extracellular adenosine in the ventral hippocampal CA1 region contribute to acute stress induced depressive-like behavior. This work improves our understanding of purinergic signaling in stress responses and may inform future research into novel therapeutic strategies for mood disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110731"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368372","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 : 2026-02-01Epub Date: 2025-10-23DOI: 10.1016/j.neuropharm.2025.110734
Rania Tarek Elkhial , Magdy M. Awny , Elsayed K. El-Sayed , Shahira Nofal
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the progressive loss of dopaminergic neurons in the basal ganglia, particularly in the substantia nigra, and the accumulation of α-synuclein into Lewy bodies. Recently, the WNT/β-catenin signaling pathway has emerged as a potential neuroprotective mechanism in PD, activated by natriuretic peptides (NPs) such as ANP, BNP, and CNP. Sacubitril/valsartan (SAC/VAL) is an FDA-approved medication for chronic heart failure. SAC contains neprilysin inhibition, while VAL is an angiotensin receptor blocker used to treat hypertension. This study aimed to determine whether SAC/VAL could activate the WNT/β-catenin pathway by increasing NP levels. To isolate the effect of SAC, VAL was administered separately. Male Wistar rats were injected with 2 mg/kg rotenone subcutaneously (S.C.) for 35 days to induce a PD-like model. VAL and SAC/VAL were administered orally at 20 mg/kg/day and 40 mg/kg/day, respectively, one week before rotenone treatment for six weeks. SAC/VAL was more effective than VAL in reducing rotenone-induced behavioral deficits, mitigating dopaminergic injury, normalizing dopamine (DA), tyrosine hydroxylase (TH), and NP levels, and activating the WNT/β-catenin pathway. SAC/VAL also suppressed oxidative stress and neuroinflammation. In conclusion, SAC/VAL exhibited greater neuroprotection against PD-induced neurodegeneration than VAL, likely due to neprilysin inhibition by the SAC component, which activates the WNT/β-catenin pathway.
{"title":"The enhanced Wnt/β-catenin pathway upregulation by sacubitril/valsartan via neprilysin inhibition compared to valsartan in the rotenone induced Parkinson's disease rat model","authors":"Rania Tarek Elkhial , Magdy M. Awny , Elsayed K. El-Sayed , Shahira Nofal","doi":"10.1016/j.neuropharm.2025.110734","DOIUrl":"10.1016/j.neuropharm.2025.110734","url":null,"abstract":"<div><div>Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the progressive loss of dopaminergic neurons in the basal ganglia, particularly in the substantia nigra, and the accumulation of α-synuclein into Lewy bodies. Recently, the WNT/β-catenin signaling pathway has emerged as a potential neuroprotective mechanism in PD, activated by natriuretic peptides (NPs) such as ANP, BNP, and CNP. Sacubitril/valsartan (SAC/VAL) is an FDA-approved medication for chronic heart failure. SAC contains neprilysin inhibition, while VAL is an angiotensin receptor blocker used to treat hypertension. This study aimed to determine whether SAC/VAL could activate the WNT/β-catenin pathway by increasing NP levels. To isolate the effect of SAC, VAL was administered separately. Male Wistar rats were injected with 2 mg/kg rotenone subcutaneously (S.C.) for 35 days to induce a PD-like model. VAL and SAC/VAL were administered orally at 20 mg/kg/day and 40 mg/kg/day, respectively, one week before rotenone treatment for six weeks. SAC/VAL was more effective than VAL in reducing rotenone-induced behavioral deficits, mitigating dopaminergic injury, normalizing dopamine (DA), tyrosine hydroxylase (TH), and NP levels, and activating the WNT/β-catenin pathway. SAC/VAL also suppressed oxidative stress and neuroinflammation. In conclusion, SAC/VAL exhibited greater neuroprotection against PD-induced neurodegeneration than VAL, likely due to neprilysin inhibition by the SAC component, which activates the WNT/β-catenin pathway.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110734"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370421","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 : 2026-02-01Epub Date: 2025-10-17DOI: 10.1016/j.neuropharm.2025.110722
Luisa Prochazkova , Josephine Marschall , Dominique Patrick Lippelt , Neil R. Schon , Martin Kuchař , Bernhard Hommel
Objective
Microdosing psychedelics has been widely reported to enhance focus and problem-solving, sparking interest in its potential to treat attentional disorders such as ADHD. However, existing studies largely rely on anecdotal evidence and lack adequate placebo control.
Methods
This study contributes to the literature by examining the longitudinal effects of microdosing psilocybin truffles in two randomized, double-blind, placebo-controlled trials conducted in semi-naturalistic settings. We assessed multiple domains, including cognitive control, memory, social cognition, subjective well-being and subjective experiences using a mix of quantitative and qualitative methods.
Results
Contrary to expectations, microdosing did not significantly affect behavioral or subjective measures compared to placebo. While some initial effects were observed in social cognition, mood, and self-reported cognitive flexibility, these did not remain significant after correcting for multiple comparisons. Regardless of condition, participants predominantly reported their subjective experiences as positive yet negative bodily feelings were enhanced in the active condition. Notably, participants remained effectively blinded throughout the trials.
Discussion: In conclusion, our findings do not support the idea that microdosing psilocybin reliably enhances cognitive or emotional functioning beyond placebo. Future research should explore individual differences in response to microdosing and examine whether specific populations might benefit from targeted microdosing interventions.
{"title":"Cognitive and subjective effects of psilocybin microdosing: Results from two double-blind placebo-controlled longitudinal trials","authors":"Luisa Prochazkova , Josephine Marschall , Dominique Patrick Lippelt , Neil R. Schon , Martin Kuchař , Bernhard Hommel","doi":"10.1016/j.neuropharm.2025.110722","DOIUrl":"10.1016/j.neuropharm.2025.110722","url":null,"abstract":"<div><h3>Objective</h3><div>Microdosing psychedelics has been widely reported to enhance focus and problem-solving, sparking interest in its potential to treat attentional disorders such as ADHD. However, existing studies largely rely on anecdotal evidence and lack adequate placebo control.</div></div><div><h3>Methods</h3><div>This study contributes to the literature by examining the longitudinal effects of microdosing psilocybin truffles in two randomized, double-blind, placebo-controlled trials conducted in semi-naturalistic settings. We assessed multiple domains, including cognitive control, memory, social cognition, subjective well-being and subjective experiences using a mix of quantitative and qualitative methods.</div></div><div><h3>Results</h3><div>Contrary to expectations, microdosing did not significantly affect behavioral or subjective measures compared to placebo. While some initial effects were observed in social cognition, mood, and self-reported cognitive flexibility, these did not remain significant after correcting for multiple comparisons. Regardless of condition, participants predominantly reported their subjective experiences as positive yet negative bodily feelings were enhanced in the active condition. Notably, participants remained effectively blinded throughout the trials.</div><div>Discussion: In conclusion, our findings do not support the idea that microdosing psilocybin reliably enhances cognitive or emotional functioning beyond placebo. Future research should explore individual differences in response to microdosing and examine whether specific populations might benefit from targeted microdosing interventions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110722"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329680","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 : 2026-02-01Epub Date: 2025-11-05DOI: 10.1016/j.neuropharm.2025.110759
Maria A. Pedrosa , Gergana Mincheva , Mar Martinez-Garcia , Lola Vazquez , Thomas P. Blackburn , Magnus Doverskog , Marta Llansola , Vicente Felipo
Golexanolone improves motor and non-motor symptoms in the 6-OHDA rat model of Parkinson's disease (PD) and reduces neuroinflammation in the striatum, without inducing dyskinesias. To understand the underlying mechanisms, we hypothesized that activated microglia in substantia nigra (SN) have increased glutaminase and glutamate production; glutamate uptake by astrocytes induces GABA release and enhanced GABAA receptors activation contributes to loss of tyrosine hydroxylase (TH) and dopamine. The study aims were to assess if: 1) the mechanisms proposed occur and are reversed by golexanolone; 2) improvement by golexanolone is maintained with pathological progression; 3) an earlier treatment start provides more beneficial effects.
Daily golexanolone treatment from one week after model induction by unilateral injection of 6-OHDA in male rats was performed. Motor function, fatigue and short-term memory were assessed after four and eight weeks. At three and nine weeks, TH, glutamate and dopamine, as well as glutaminase in microglia and GABA in astrocytes were analyzed.
6-OHDA rats show microglia activation in SN, with increased glutaminase and glutamate. Increased glutamate is associated with reduced GABA into astrocytes and increased extracellular GABA, which enhances GABAA receptors activation in neurons, contributing to loss of TH and dopamine, and altering TrkB signaling. Golexanolone reduces activation of microglia at early and long time after 6-OHDA injection, reduces activation of the glutaminase-glutamate-GABA-TH-dopamine pathway at three weeks after surgery and preserves TrkB membrane expression associated with dopamine receptors, despite the loss of dopamine, at a longer time. Both mechanisms contribute to sustained improvement of fatigue and motor and cognitive functions.
Early treatment affords more beneficial effects than late treatment on PD symptoms. Golexanolone affords sustained improvement of PD symptoms in the rat model by reducing neuroinflammation, increasing dopaminergic signaling and therefore could be considered for clinical evaluation in patients with PD.
{"title":"Golexanolone affords sustained improvement of Parkinson's symptoms in rats by reducing microglia activation that restores the glutamate-GABA-dopamine pathway","authors":"Maria A. Pedrosa , Gergana Mincheva , Mar Martinez-Garcia , Lola Vazquez , Thomas P. Blackburn , Magnus Doverskog , Marta Llansola , Vicente Felipo","doi":"10.1016/j.neuropharm.2025.110759","DOIUrl":"10.1016/j.neuropharm.2025.110759","url":null,"abstract":"<div><div>Golexanolone improves motor and non-motor symptoms in the 6-OHDA rat model of Parkinson's disease (PD) and reduces neuroinflammation in the striatum, without inducing dyskinesias. To understand the underlying mechanisms, we hypothesized that activated microglia in substantia nigra (SN) have increased glutaminase and glutamate production; glutamate uptake by astrocytes induces GABA release and enhanced GABA<sub>A</sub> receptors activation contributes to loss of tyrosine hydroxylase (TH) and dopamine. The study aims were to assess if: 1) the mechanisms proposed occur and are reversed by golexanolone; 2) improvement by golexanolone is maintained with pathological progression; 3) an earlier treatment start provides more beneficial effects.</div><div>Daily golexanolone treatment from one week after model induction by unilateral injection of 6-OHDA in male rats was performed. Motor function, fatigue and short-term memory were assessed after four and eight weeks. At three and nine weeks, TH, glutamate and dopamine, as well as glutaminase in microglia and GABA in astrocytes were analyzed.</div><div>6-OHDA rats show microglia activation in SN, with increased glutaminase and glutamate. Increased glutamate is associated with reduced GABA into astrocytes and increased extracellular GABA, which enhances GABA<sub>A</sub> receptors activation in neurons, contributing to loss of TH and dopamine, and altering TrkB signaling. Golexanolone reduces activation of microglia at early and long time after 6-OHDA injection, reduces activation of the glutaminase-glutamate-GABA-TH-dopamine pathway at three weeks after surgery and preserves TrkB membrane expression associated with dopamine receptors, despite the loss of dopamine, at a longer time. Both mechanisms contribute to sustained improvement of fatigue and motor and cognitive functions.</div><div>Early treatment affords more beneficial effects than late treatment on PD symptoms. Golexanolone affords sustained improvement of PD symptoms in the rat model by reducing neuroinflammation, increasing dopaminergic signaling and therefore could be considered for clinical evaluation in patients with PD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110759"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145467574","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 : 2026-02-01Epub Date: 2025-10-14DOI: 10.1016/j.neuropharm.2025.110723
Meng-Yao Wang , Yuan-Hong Deng , Xiao-Feng Ran , Yang Peng , Wen-Jing Ren , Si-Si Lin , Patrizia Rubini , Peter Illes , Yong Tang
Astrocytes play a vital role in neuroinflammatory processes within the central nervous system (CNS). Increasing evidence suggests that purinergic G protein-coupled receptor P2Y14 is associated with neuroinflammation. However, the expression, distribution, and function of P2Y14 in astrocytes remain unclear. This study aimed to investigate the expression of P2Y14 receptors in astrocytes and their regulatory role in astrocytic inflammatory responses. P2Y14 expression was confirmed in primary astrocytes isolated from the mouse cerebral cortex using immunofluorescence techniques. Western blot and RT-qPCR analyses showed that lipopolysaccharide (LPS) stimulation significantly increased P2Y14 expression in astrocytes. The antagonist of P2Y14 receptor, 4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl2-naphthoic acid (PPTN) reduced glial fibrillary acidic protein (GFAP) expression, while the agonist of P2Y14 receptor, uridine diphosphate glucose (UDPG) promoted it in astrocytes. Mechanistically, PPTN inhibited the expression of signal transducer and activator of transcription 1 (STAT1) and its phosphorylated form (p-STAT1), while UDPG enhanced the activation of STAT1/p-STAT1. Treatment with the P2Y14 antagonist PPTN resulted in significant inhibition of interleukin (IL)-6, IL-18, and tumor necrosis factor-alpha (TNF-α) release. By contrast, stimulation of the P2Y14 receptor with its agonist UDPG induced a substantial increase in the levels of these inflammatory mediators. These results were further validated in the cell line of mouse astrocyte C8-D1A using pharmacological approaches and lentiviral transduction to modulate P2Y14 expression. This study confirmed that astrocytes express functional P2Y14 receptors and demonstrated their key role in regulating astrocyte activation and inflammatory responses. This regulation may be achieved through the UDPG/P2Y14-STAT1 signaling axis, which provides a new molecular basis for understanding the regulatory mechanisms of astrocytic inflammatory responses.
{"title":"UDPG/P2Y14-STAT1 axis mediates LPS-induced reactive astrogliosis","authors":"Meng-Yao Wang , Yuan-Hong Deng , Xiao-Feng Ran , Yang Peng , Wen-Jing Ren , Si-Si Lin , Patrizia Rubini , Peter Illes , Yong Tang","doi":"10.1016/j.neuropharm.2025.110723","DOIUrl":"10.1016/j.neuropharm.2025.110723","url":null,"abstract":"<div><div>Astrocytes play a vital role in neuroinflammatory processes within the central nervous system (CNS). Increasing evidence suggests that purinergic G protein-coupled receptor P2Y<sub>14</sub> is associated with neuroinflammation. However, the expression, distribution, and function of P2Y<sub>14</sub> in astrocytes remain unclear. This study aimed to investigate the expression of P2Y<sub>14</sub> receptors in astrocytes and their regulatory role in astrocytic inflammatory responses. P2Y<sub>14</sub> expression was confirmed in primary astrocytes isolated from the mouse cerebral cortex using immunofluorescence techniques. Western blot and RT-qPCR analyses showed that lipopolysaccharide (LPS) stimulation significantly increased P2Y<sub>14</sub> expression in astrocytes. The antagonist of P2Y<sub>14</sub> receptor, 4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl2-naphthoic acid (PPTN) reduced glial fibrillary acidic protein (GFAP) expression, while the agonist of P2Y<sub>14</sub> receptor, uridine diphosphate glucose (UDPG) promoted it in astrocytes. Mechanistically, PPTN inhibited the expression of signal transducer and activator of transcription 1 (STAT1) and its phosphorylated form (p-STAT1), while UDPG enhanced the activation of STAT1/p-STAT1. Treatment with the P2Y<sub>14</sub> antagonist PPTN resulted in significant inhibition of interleukin (IL)-6, IL-18, and tumor necrosis factor-alpha (TNF-α) release. By contrast, stimulation of the P2Y<sub>14</sub> receptor with its agonist UDPG induced a substantial increase in the levels of these inflammatory mediators. These results were further validated in the cell line of mouse astrocyte C8-D1A using pharmacological approaches and lentiviral transduction to modulate P2Y<sub>14</sub> expression. This study confirmed that astrocytes express functional P2Y<sub>14</sub> receptors and demonstrated their key role in regulating astrocyte activation and inflammatory responses. This regulation may be achieved through the UDPG/P2Y<sub>14</sub>-STAT1 signaling axis, which provides a new molecular basis for understanding the regulatory mechanisms of astrocytic inflammatory responses.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110723"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308639","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 : 2026-02-01Epub Date: 2025-11-07DOI: 10.1016/j.neuropharm.2025.110756
Ariana N. Pritha , Andrea A. Pasmay , Alissa N. Jones , Justin R. Carter , Shahani Noor
Prenatal alcohol exposure (PAE) exerts lingering effects on neuroimmune function. Based on existing literature on overlapping neuroimmune actions of PAE and opioid pain therapies, here, we examined pain sensitivity (allodynia) in adult male PAE mice following opioid (morphine) treatment. Using a previously characterized model of minor nerve injury, we show that morphine treatment promotes allodynia in PAE mice, not in control mice. This study characterized spinal transcriptomics and explored potential roles of non-coding RNAs (ncRNAs) underlying this paradoxical effect of morphine in PAE mice. Utilizing next-generation bulk RNA sequencing, we generated a comprehensive profile of spinal mRNAs, circular RNAs (circRNAs), and linear long non-coding RNAs (lncRNAs) from morphine-treated allodynic PAE mice. This unbiased approach identified endogenous immune activators (Tcf7l2, Dnaj1, Hmgb1, Hsph1) and the involvement of oxidative stress, hemoglobin genes in PAE mice. Furthermore, a unique spinal circRNA and lncRNA profile, featuring >200 differentially expressed ncRNAs, emerged from morphine-treated PAE mice. Notably, lncRNA and circRNAs with proinflammatory roles, such as circPan3, circRab11, and lncSnhg14, were upregulated, whereas circNr3c2 and circAnkrd12, which are known to exert protective roles against inflammation, were downregulated in PAE mice. Pathways and interaction analysis revealed that these genes are linked to inflammation, cellular stress response, and neuronal-glial interactions that may contribute to pain pathophysiology. Together, these data provide preclinical evidence that PAE and morphine interaction involves spinal proinflammatory activation and are predictive of adverse responses to opioid pain therapy. Dysregulation of ncRNAs may play novel mechanistic roles in neuroimmune dysfunction and allodynic susceptibility under PAE conditions.
{"title":"Prenatal alcohol exposure induces circular and linear long non-coding RNAs, and protein-coding genes linked to proinflammatory neuroimmune function, promoting nerve injury-induced allodynia following morphine treatment","authors":"Ariana N. Pritha , Andrea A. Pasmay , Alissa N. Jones , Justin R. Carter , Shahani Noor","doi":"10.1016/j.neuropharm.2025.110756","DOIUrl":"10.1016/j.neuropharm.2025.110756","url":null,"abstract":"<div><div>Prenatal alcohol exposure (PAE) exerts lingering effects on neuroimmune function. Based on existing literature on overlapping neuroimmune actions of PAE and opioid pain therapies, here, we examined pain sensitivity (allodynia) in adult male PAE mice following opioid (morphine) treatment. Using a previously characterized model of minor nerve injury, we show that morphine treatment promotes allodynia in PAE mice, not in control mice. This study characterized spinal transcriptomics and explored potential roles of non-coding RNAs (ncRNAs) underlying this paradoxical effect of morphine in PAE mice. Utilizing next-generation bulk RNA sequencing, we generated a comprehensive profile of spinal mRNAs, circular RNAs (circRNAs), and linear long non-coding RNAs (lncRNAs) from morphine-treated allodynic PAE mice. This unbiased approach identified endogenous immune activators (<em>Tcf7l2, Dnaj1, Hmgb1, Hsph1</em>) and the involvement of oxidative stress, hemoglobin genes in PAE mice. Furthermore, a unique spinal circRNA and lncRNA profile, featuring >200 differentially expressed ncRNAs, emerged from morphine-treated PAE mice. Notably, lncRNA and circRNAs with proinflammatory roles, such as <em>circPan3</em>, <em>circRab11,</em> and <em>lncSnhg14,</em> were upregulated, whereas circ<em>Nr3c2</em> and <em>circAnkrd12</em>, which are known to exert protective roles against inflammation, were downregulated in PAE mice. Pathways and interaction analysis revealed that these genes are linked to inflammation, cellular stress response, and neuronal-glial interactions that may contribute to pain pathophysiology. Together, these data provide preclinical evidence that PAE and morphine interaction involves spinal proinflammatory activation and are predictive of adverse responses to opioid pain therapy. Dysregulation of ncRNAs may play novel mechanistic roles in neuroimmune dysfunction and allodynic susceptibility under PAE conditions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"283 ","pages":"Article 110756"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482505","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 : 2026-01-01Epub Date: 2025-10-17DOI: 10.1016/j.neuropharm.2025.110720
Minglong Zhang , Jian Wang , Hongyu Yang , Yun Lu , Hailei Yu , Bing Xie , Ludi Zhang , Bin Cong , Chunling Ma , Di Wen
Opioid addiction remains a critical public health challenge, yet the underlying neurobiological mechanisms remain incompletely understood. This study investigated the role of small-conductance calcium-activated potassium (SK) channels in the nucleus accumbens core (NAcC) in opioid-related behaviors. Using conditioned place preference (CPP) and intravenous self-administration (IVSA) models in mice, we observed a reduction in the excitability of NAcC medium spiny neurons (MSNs) concomitant with an increase in SK3 channel expression and SK-mediated currents during morphine-induced CPP. Pharmacological activation of SK channels with 1-EBIO enhanced morphine CPP, whereas blockade with apamin attenuated it. Viral-mediated SK3 overexpression in NAcC potentiated both morphine CPP and heroin IVSA, while SK3 knockdown suppressed these behaviors. Electrophysiological recordings confirmed that SK3 modulation bidirectionally regulated MSN excitability and medium afterhyperpolarization (mAHP). These findings demonstrate that SK3 channels in NAcC critically regulate opioid reward and reinforcement by modulating neuronal excitability, suggesting SK3 channel as a potential therapeutic target for opioid addiction.
{"title":"Role of SK3 channels in the nucleus accumbens core in modulating opioid-induced addiction behaviors","authors":"Minglong Zhang , Jian Wang , Hongyu Yang , Yun Lu , Hailei Yu , Bing Xie , Ludi Zhang , Bin Cong , Chunling Ma , Di Wen","doi":"10.1016/j.neuropharm.2025.110720","DOIUrl":"10.1016/j.neuropharm.2025.110720","url":null,"abstract":"<div><div>Opioid addiction remains a critical public health challenge, yet the underlying neurobiological mechanisms remain incompletely understood. This study investigated the role of small-conductance calcium-activated potassium (SK) channels in the nucleus accumbens core (NAcC) in opioid-related behaviors. Using conditioned place preference (CPP) and intravenous self-administration (IVSA) models in mice, we observed a reduction in the excitability of NAcC medium spiny neurons (MSNs) concomitant with an increase in SK3 channel expression and SK-mediated currents during morphine-induced CPP. Pharmacological activation of SK channels with 1-EBIO enhanced morphine CPP, whereas blockade with apamin attenuated it. Viral-mediated SK3 overexpression in NAcC potentiated both morphine CPP and heroin IVSA, while SK3 knockdown suppressed these behaviors. Electrophysiological recordings confirmed that SK3 modulation bidirectionally regulated MSN excitability and medium afterhyperpolarization (mAHP). These findings demonstrate that SK3 channels in NAcC critically regulate opioid reward and reinforcement by modulating neuronal excitability, suggesting SK3 channel as a potential therapeutic target for opioid addiction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"282 ","pages":"Article 110720"},"PeriodicalIF":4.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329653","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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