Neuropharmacology[JOURNAL]
Sun
200 papers
Inhibiting AP2M1-mediated GluA2 endocytosis by G2CT peptide ameliorates synaptic and memory deficits in Alzheimer's Disease.
Xue M, Pang Y, Tian Q … +10 more , Dai C, Tian N, Yuan H, Xu B, Fan Y, Peng Y, Hao A, Yan X, Zhang Q, Dong Z
Neuropharmacology · 2026 Jun · PMID 41740904 · Publisher ↗
Abnormal endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) subunit GluA2 is implicated in early synaptic dysfunction in Alzheimer's disease (AD). In this study, we utilized human brai...
Abnormal endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) subunit GluA2 is implicated in early synaptic dysfunction in Alzheimer's disease (AD). In this study, we utilized human brain tissue samples from both male and female autopsy specimens (including 6 clinically diagnosed AD patients and 6 normal controls without central nervous system pathology), male and female 5 × FAD five-transgenic mice and their wild-type (WT) littermates (C57BL/6J genetic background), as well as mouse neuroblastoma Neuro-2a (N2A) cells, to demonstrate that GluA2 undergoes enhanced endocytosis in APP-overexpressing N2A cells. This enhanced endocytosis is driven by an increased interaction with the μ subunit of the adaptor protein complex 2 (AP2M1), without affecting total GluA2 protein levels. Targeting this interaction with the competitive peptide G2CT effectively restores GluA2 membrane expression and improves synaptic function in vivo. Furthermore, G2CT rescues cognitive deficits in male and female 5 × FAD AD mouse models, without detectable alterations in amyloid precursor protein processing or amyloid-beta (Aβ) production under the experimental conditions used. These findings identify the GluA2-AP2M1 interaction as a critical mechanism of early synaptic dysfunction and highlight a therapeutic strategy for AD that acts downstream of amyloid-β signaling and ameliorates synaptic and cognitive deficits without altering amyloid pathology.
The β-amyloid-induced increased tonic conductance, impaired long-term potentiation and cognitive deficits characteristic of Alzheimer's disease are reversed by an α5 inverse agonist of the GABA type A receptor.
O'Connell A, Calvo-Flores Guzmán B, Zhai Y … +9 more , Keighron CN, Boix J, Peppercorn K, Tate WP, Waldvogel HJ, Faull RL, Montgomery JM, Quinlan L, Kwakowsky A
Neuropharmacology · 2026 Jun · PMID 41740903 · Publisher ↗
Alzheimer's disease is a chronic, progressive neurodegenerative disorder characterized by cognitive impairment, which may arise from disruptions in the excitatory/inhibitory balance within the brain. Gamma-aminobutyric a...
Alzheimer's disease is a chronic, progressive neurodegenerative disorder characterized by cognitive impairment, which may arise from disruptions in the excitatory/inhibitory balance within the brain. Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the central nervous system, plays a crucial role in maintaining the excitatory/inhibitory balance and regulating neuronal activity involved in memory. In Alzheimer's disease, changes in α5 GABA A type receptor expression and activity increase tonic inhibition, disturbing the neuronal excitatory/inhibitory balance and ultimately impairing cognitive processes. Therefore, targeting the α5 GABA A receptor offers a promising therapeutic strategy to mitigate impairments in these processes. This study examined the potential of an α5 GABA A receptor-selective inverse agonist, α5IA, for treating β-amyloid-induced cognitive deficits and the underlying mechanism of action, using ex vivo microelectrode array and patch clamp electrophysiology. The inverse agonist, α5IA, improved impaired long-term potentiation, reduced elevated tonic conductance in CA1 hippocampal neurons and improved long-term spatial memory deficits induced by β-amyloid. These findings highlight α5IA's ability to restore excitatory/inhibitory balance and, thereby, cognitive function. The selective targeting of α5 GABA type A receptors with α5 GABA A receptor inverse agonists, such as α5IA, represents a promising direction for developing novel Alzheimer's disease therapies.
Dopamine, γ-aminobutyric acid, and glutamate balance in the nucleus accumbens shell: Differential effects of cannabinoid 1 receptor agonists Δ-Tetrahydrocannabinol, AM11101, and AM8936.
Smith EC, Iliopoulos-Tsoutsouvas C, Georgiadis MO … +4 more , Nikas SP, Brijlall K, Makriyannis A, Desai RI
Neuropharmacology · 2026 Jun · PMID 41740902 · Publisher ↗
Despite being the most prevalently abused illicit drug class, the neurochemical effects of cannabinoids (CBs) in key reward-related brain regions are not fully understood. Here, we used in vivo microdialysis combined wit...
Despite being the most prevalently abused illicit drug class, the neurochemical effects of cannabinoids (CBs) in key reward-related brain regions are not fully understood. Here, we used in vivo microdialysis combined with liquid chromatograph mass spectrometry to delineate how single, intraperitoneal injections of delta-9-tetrahydrocannabinol (Δ-THC), and synthetic partial (AM11101) and full (AM8936) CB agonists, impacted dopamine (DA), glutamate (Glu), and γ-aminobutyric acid (GABA) balance in the nucleus accumbens (nAcc) shell of male mice for 5 h post-administration, as well as conditioned place preference to determine their rewarding effects. Low doses of Δ-THC increased DA and GABA, whereas AM8936 increased all three neurotransmitters. High doses of Δ-THC and AM8936 decreased DA, while only high doses of AM8936 decreased GABA. AM11101 failed to substantially alter all three neurotransmitters. Correlation analysis revealed a significant DA-GABA and Glu-GABA relationship for Δ-THC at early time points. Though their effects differed in timing, both AM11101 and AM8936 produced significant relationships between all three neurotransmitters. In conditioned place preference (CPP) studies, Δ-THC and AM8936, but not AM11101, significantly increased CPP score. Together, these data demonstrate that CB agonists differentially impact DA, GABA, and Glu levels in the nAcc shell, which directly correlate to reward-related behavioral effects. The lack of reward-related neurochemical or behavioral effects of AM11101, coupled with its superior biochemical profile, suggests that this partial CB agonist is unique and warrants further studies on its potential as a CB-based pharmacotherapeutic for clinical indications.
Autism-related phenotypes in a heterozygous Scn2a mouse model and their partial rescue via a potassium channel opener.
Ismail H, Abdalla SM, Carman ZT … +3 more , Sherif M, Lundstrom BN, Eltokhi A
Neuropharmacology · 2026 Jun · PMID 41724236 · Publisher ↗
The voltage-gated sodium channel Na1.2 is frequently implicated in neurodevelopmental and neurological disorders, including developmental and epileptic encephalopathy (DEE) and autism spectrum disorder (ASD). Genotype-ph...
The voltage-gated sodium channel Na1.2 is frequently implicated in neurodevelopmental and neurological disorders, including developmental and epileptic encephalopathy (DEE) and autism spectrum disorder (ASD). Genotype-phenotype studies show that Na1.2 mutations with mixed gain- (GoF) and loss-of-function (LoF) effects are associated with the most severe clinical outcomes. The R853Q mutation in the second gating charge of Domain II decreases current density by 50-60% and was initially classified as a LoF mutation, likely resulting in reduced neuronal firing. However, this does not fully explain its recurrent association with DEE and severe forms of ASD. Our recent findings indicate that R853Q induces a gating pore current (I) in the resting state, introducing a GoF component that may increase cortical neuronal excitability. This mixed GoF/LoF effect may underlie the strong clinical phenotypes observed in patients carrying this mutation. To explore this, we generated a mouse model carrying the orthologous R854Q mutation and performed an initial characterization of this model. Behavioral analyses revealed that heterozygous Na1.2(R854Q) mice exhibit ASD-like phenotypes, including impaired social interaction and social novelty, repetitive rearing, and increased risk-taking behaviors. In silico modeling suggests that, in cortical neurons, the net effect of the R854Q mutation is a reduction in neuronal excitability due to decreased sodium conductance, although I alone increases excitability and partially offsets this reduction. Notably, acute administration of retigabine, a potassium channel opener, rescues specific ASD-related phenotypes, possibly by restoring decreased firing through reduction of slow sodium inactivation. Comparative analysis with Scn2a knockout models, which show similar current reduction, highlights the unique severity of R854Q, suggesting a role of I in modulating neurobehavioral outcomes and informing potential therapeutic strategies.
Assessment of high-efficacy agonism in synthetic cannabinoid receptor agonists containing l-tert-leucinate.
Lucaj C, Oh SJ, Pitha C … +3 more , Davis J, Shi L, Yano H
Neuropharmacology · 2026 Jun · PMID 41713499 · Publisher ↗
Synthetic cannabinoid receptor agonists (SCRAs) represent a class of new psychoactive substances that pose great health risks attributed to their wide-ranging and severe adverse effects. Recent evidence has shown that SC...
Synthetic cannabinoid receptor agonists (SCRAs) represent a class of new psychoactive substances that pose great health risks attributed to their wide-ranging and severe adverse effects. Recent evidence has shown that SCRAs with key moieties can confer superagonism, yet this phenomenon is still not well understood. Here we report structure-activity relationships (SARs) of modular SCRAs contributing to superagonism by comparing eight compounds differing by their head moiety (l-valinate vs. l-tert-leucinate), core moiety (indole vs. indazole), and tail moiety (5-fluoropentyl vs. 4-fluorobenzyl) through different modes of bioluminescence resonance energy transfer (BRET) assays. We found that the l-tert-leucinate head moiety and indazole core moiety conferred superagonism across multiple Gα proteins and β-arrestin-2. After generating the cannabinoid type 1 receptor (CB1R) mutant constructs, we found that transmembrane 2 (TM2) interactions to the head moiety of tested SCRAs at F170, F174, F177, and H178 are key to eliciting activity. Finally, we found that l-tert-leucinate SCRAs confer a high-efficacy response in ex vivo slice electrophysiology.
Chronic ethanol drinking alters medial prefrontal cortex and nucleus accumbens astrocyte translatome and extracellular matrix glycosaminoglycans.
Hashimoto JG, Ozburn AR, Reed C … +11 more , Erk J, Song Y, Yang J, Xia K, Zhang F, Yu Y, Fei SS, Gao L, Linhardt RJ, Phillips TJ, Guizzetti M
Neuropharmacology · 2026 May · PMID 41713498 · Full text
Alcohol Use Disorder is a leading preventable cause of morbidity and mortality, yet knowledge of mechanisms driving ethanol-related neuroplasticity remains incomplete. While research has traditionally focused on neuronal...
Alcohol Use Disorder is a leading preventable cause of morbidity and mortality, yet knowledge of mechanisms driving ethanol-related neuroplasticity remains incomplete. While research has traditionally focused on neuronal signaling, emerging evidence implicates astrocytes in addiction-related adaptations. Here, we investigated the astrocyte-specific molecular consequences of chronic ethanol consumption in the prefrontal cortex and nucleus accumbens, two brain regions critical for executive control and reward processing. Using Translating Ribosome Affinity Purification RNA-seq and bulk RNA-seq in Aldh1l1-EGFP/Rpl10a mice, expressing an EGFP tag on astrocyte ribosomes, we identified hundreds of differentially translated astrocytic genes following chronic continuous two-bottle choice ethanol drinking. Sex-specific analyses revealed a higher number of astrocytic changes in the female PFC and male NAc. Pathway enrichment highlighted extracellular matrix remodeling, synaptic signaling, mitochondrial function, and immune-related pathways. Analyses of individual drinking levels further demonstrated distinct correlations between ethanol intake and astrocytic translation. The major components of the brain extracellular matrix are chondroitin sulfate proteoglycans, produced primarily by astrocytes and covalently bound to chondroitin sulfate glycosaminoglycan chains. Complementary mass spectrometry/liquid chromatography analyses of chondroitin sulfate, heparan sulfate, and hyaluronic acid glycosaminoglycan disaccharides revealed ethanol-induced alterations in chondroitin sulfate glycosaminoglycan sulfation patterns, with additional baseline differences identified between selectively bred high- and low-ethanol preference lines. Together, these findings indicate that astrocytes undergo profound sex- and region-specific adaptations to chronic ethanol, implicating extracellular matrix and glycosaminoglycan remodeling as key risk-factors for and mediators of chronic ethanol-related neuroplasticity.
Mediodorsal thalamus of alcohol-dependent mice shows genetic and physiological adaptations and alcohol-biased calcium signaling.
Martin JC, Reeves KC, Carter KA … +13 more , Davis M, Schneider A, Meade E, Lebonville CL, Nimitvilai-Roberts S, Hoffman M, Woodward JJ, Loewinger G, Smith RJ, Lopez MF, Becker HC, Mulholland PJ, Rinker JA
Neuropharmacology · 2026 Jun · PMID 41707784 · Full text
Alcohol Use Disorder (AUD) is a significant health concern characterized by cognitive dysfunction and an inability to control alcohol intake, leading to severe social and health consequences. It is crucial to uncover neu...
Alcohol Use Disorder (AUD) is a significant health concern characterized by cognitive dysfunction and an inability to control alcohol intake, leading to severe social and health consequences. It is crucial to uncover neuroadaptations and cellular mechanisms responsible for poor decisions surrounding alcohol drinking. Although the mediodorsal thalamus (MD) is an essential brain region for cognitive function and reward-guided choices, the effects of alcohol dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol over natural rewards (i.e., sucrose) are not well understood. Genetic and physiological adaptations in the MD were assessed in mice treated with the chronic intermittent ethanol (CIE) exposure model of dependence, which increased alcohol intake and preference during choice sessions for water or sucrose in males and females. Results indicated that CIE exposure induced time-dependent changes in c-Fos and transcript expression and increased excitability of MD neurons during withdrawal. Enrichment analysis of alcohol-sensitive genes revealed dysregulation of genes that control glial function and axonal myelination. Fiber photometry recordings demonstrated that MD activity was elevated at the start of and after licking bouts for alcohol, water, or sucrose, and the signal for alcohol was significantly higher than the signal for other solutions in control and alcohol dependent mice. These findings demonstrate that CIE exposure causes alcohol-biased choice behaviors and genetic and physiological neuroadaptations in the MD, with MD neurons showing a unique response to alcohol over other solutions.
Diminazene attenuates astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in Alzheimer's Disease Model.
Xu Z, Li X, Wang S … +7 more , Lyu J, Zhu S, Chen S, Li Y, Zhang Y, Wang F, Duan R
Neuropharmacology · 2026 May · PMID 41698644 · Publisher ↗
PURPOSE: Diminazene (DIZE), an agonist of the Ang-(1-7) system, has been proven to suppress astrocytic neuroinflammatory responses in Alzheimer's disease (AD). NADPH oxidase 4 (NOX4) is abundantly expressed in astrocytes...
PURPOSE: Diminazene (DIZE), an agonist of the Ang-(1-7) system, has been proven to suppress astrocytic neuroinflammatory responses in Alzheimer's disease (AD). NADPH oxidase 4 (NOX4) is abundantly expressed in astrocytes and critically mediates oxidative stress damage and ferroptosis. However, the mode of DIZE in AD-related NOX4 overactivation and ferroptosis remains to be revealed. METHODS: Male APP/PS1 mice received DIZE and the ferroptosis inhibitor Liproxstatin-1 (LIP) treatment. Behavioral tests, Nissl staining, Western blotting, ELISA and immunofluorescence were performed to evaluate the effects of DIZE on neuronal loss, synaptic damage, inflammation and iron accumulation. Astrocytes from APP/PS1 mice were underwent high-throughput miRNA sequencing to identity the most differentially expressed miRNAs after DIZE administration. Subsequently, the role of this miRNA in DIZE's anti-ferroptosis impact within primary astrocytes was explored. RESULTS: DIZE markedly reduced iron accumulation while lowering oxidative stress and inflammation in APP/PS1 mice. Simultaneously, DIZE significantly mitigated cognitive deficits and synaptic injury in APP/PS1 mice. DIZE suppressed the expression level of NOX4 and upregulated miR-10b-3p. Importantly, miR-10b-3p levels were notably elevated in astrocytes of APP/PS1 mice administered DIZE, targeting the NOX4 protein. Inhibition of miR-10b-3p expression significantly reversed the therapeutic effect of DIZE. CONCLUSION: These findings indicate that DIZE suppresses astrocytic oxidative stress and neuronal ferroptosis via miR-10b-3p/NOX4 axis in AD model.
Nicotine produces a sex- and subregion-specific hypoglutamatergic state in rodent amygdala which can be reversed by motor-skill training.
Lucente E, Domi A, Ericson M … +1 more , Adermark L
Neuropharmacology · 2026 Jun · PMID 41692157 · Publisher ↗
Nicotine abstinence is associated with negative affect and a high risk of relapse, but the neurophysiological underpinnings have not been fully outlined. Considering the role of the amygdala in emotional processing and s...
Nicotine abstinence is associated with negative affect and a high risk of relapse, but the neurophysiological underpinnings have not been fully outlined. Considering the role of the amygdala in emotional processing and stress regulation, changes in neurotransmission were assessed in the amygdala during nicotine withdrawal in female and male rats and putative molecular underpinnings were examined using proteomic analysis. Behavioral transformations elicited by repeated nicotine exposure were assessed in an open field arena and on the elevated plus maze (EPM). In addition, rats were trained on the Rotarod to explore if motor skill training could restore neurotransmission during nicotine abstinence. Repeated administration of nicotine produced behavioral sensitization in both male and female Wistar rats, with a more pronounced effect on female rats. While anxiety-like behavior on the EPM was not significantly affected, electrophysiological recordings demonstrated a hypoglutamatergic state, with reduced frequency and amplitude of spontaneous activity and impaired maintenance of action potential firing. Changes in neurotransmission were specific to the basolateral amygdala (BLA) of female rats and not observed in the central amygdala. Proteomic analyses identified parallel transformations in proteins involved in vesicle release and potassium and sodium homeostasis, which might contribute to synaptic impairments. Neurotransmission was restored following five days of motor skill training on the rotarod. In conclusion, nicotine produces sustained suppression of glutamatergic neurotransmission in the female BLA, which putatively could contribute to emotional dysregulation and enhanced relapse risk. Importantly, motor skill training was sufficient to restore neurotransmission, highlighting the therapeutic potential of exercise in nicotine dependence.
TAAR1 activation normalizes dopamine signaling and decreases alcohol intake in SRKO mice after adolescent ethanol exposure.
Houdant C, Rouanet C, Bouet V … +5 more , Freret T, Boulouard M, Leo D, Jeanblanc J, Naassila M
Neuropharmacology · 2026 May · PMID 41692156 · Publisher ↗
Glutamatergic and dopaminergic dysregulations are major features of alcohol use disorder (AUD). The trace amine-associated receptor 1 (TAAR1), which modulates both systems, has emerged as a promising therapeutic target,...
Glutamatergic and dopaminergic dysregulations are major features of alcohol use disorder (AUD). The trace amine-associated receptor 1 (TAAR1), which modulates both systems, has emerged as a promising therapeutic target, although the underlying mechanisms remain unclear. Here, we used male serine racemase knockout (SRKO) mice, a model of chronic NMDA receptor hypofunction and mesolimbic hyperdopaminergia, to investigate how TAAR1 activation shapes alcohol consumption and ethanol-induced dopamine release. Ethanol intake was measured during adolescence and adulthood, and ex vivo fast-scan cyclic voltammetry was used to examine dopamine release in the nucleus accumbens (NAc) core. SRKO mice consumed less alcohol than wild-type controls during adolescence, an effect amplified in adulthood and associated with a blunted dopaminergic response to acute ethanol. Adult SRKO mice previously exposed to alcohol during adolescence displayed an enhanced sensitivity to the TAAR1 full agonist RO5166017, which markedly reduced alcohol consumption and normalized dopamine signaling across groups, leading to similar ethanol-evoked decreases in NAc dopamine release. These findings show that NMDA receptor hypofunction and adolescent alcohol exposure increase TAAR1 signaling sensitivity, making TAAR1 activation particularly effective at reducing alcohol consumption and normalizing dopamine function. This work supports TAAR1 as a relevant molecular target for AUD, especially in conditions involving glutamatergic dysfunction and a history of adolescent alcohol exposure.
Pyk2-PSD95 activation alleviates cognitive dysfunction by modulation of hippocampal synaptic structural plasticity via NMDAR2A in mice with neuropathic pain.
Song Q, Zhang Y, Zhang Z … +8 more , Liu X, Hou R, Jia H, Wang S, Sun L, Liu Y, Zhang R, Liang Y
Neuropharmacology · 2026 May · PMID 41690512 · Publisher ↗
Neuropathic pain is frequently accompanied by cognitive impairments, which exacerbate the quality of life for chronic pain patients. Previous studies have demonstrated that the hippocampus as a key region involved in cog...
Neuropathic pain is frequently accompanied by cognitive impairments, which exacerbate the quality of life for chronic pain patients. Previous studies have demonstrated that the hippocampus as a key region involved in cognitive dysfunction. In this study, we discovered that cognitive impairments in neuropathic pain mice were associated with decreased hippocampal expression of PTK2B (which encodes Pyk2) and PSD-95, as revealed by RNA sequencing. Further analysis of the results of RNA sequencing indicated that differentially expressed genes (DEGs) were primarily enriched in postsynaptic specialization cellular components and calcium signaling pathways. These findings suggest that synaptic alterations are closely related to cognitive impairments in neuropathic pain mice. We also observed a reduction in the density of dendritic spines on hippocampal synapses in mice suffering from neuropathic pain with cognitive deficits. Notably, modulating PTK2B expression in the bilateral hippocampus through stereotactic injection can influence cognitive function and alter PSD-95 expression in neuropathic pain mice. Overexpression of PTK2B in the dorsal hippocampus of these mice alleviated cognitive dysfunction by modifying the synaptic cleft and restoring the diminished density of dendritic spines, while enhancing PSD-95 and NMDAR2A expression, but not NMDAR2B. Additionally, co-immunoprecipitation (Co-IP) experiments demonstrated a direct interaction between Pyk2 and PSD-95, which modulates the glutamate receptor NMDAR2A. In conclusion, our findings suggest that the Pyk2-PSD95 interaction modulates synaptic structural plasticity via NMDAR2A and contributes to cognitive impairment in chronic neuropathic pain, offering potential molecular targets for therapeutic intervention.
Ivermectin reduces withdrawal-induced alcohol intake in rats: Association with CeA GABAergic enhancement and P2rx4 genetic liability.
Campo P, Qiao R, Doyle MR … +5 more , Munro D, Johnson BB, Palmer AA, Kallupi M, de Guglielmo G
Neuropharmacology · 2026 May · PMID 41690511 · Full text
Although FDA-approved medications for alcohol use disorder are available, their efficacy varies across patients, highlighting the need for novel therapeutics that address inter-individual differences in disease etiology...
Although FDA-approved medications for alcohol use disorder are available, their efficacy varies across patients, highlighting the need for novel therapeutics that address inter-individual differences in disease etiology and treatment response. Genetic models, particularly heterogeneous stock (HS) rats, recapitulate human-like genetic diversity and behavioral heterogeneity, enabling the dissection of individual differences in vulnerability to AUD and pharmacotherapeutic sensitivity. P2X4 receptors, which are encoded by the gene P2rx4, are ATP-gated ion channels are inhibited by ethanol and abundantly expressed in neurons found in reward and stress circuits. P2X4 receptors have emerged as key modulators of ethanol sensitivity and consumption in preclinical models. Here, we genetically predicted P2rx4 expression in whole brain in 131 male and female HS rats exposed to chronic intermittent ethanol vapor and phenotyped for self-administration during acute abstinence. Rats were dichotomized into genetically predicted high and low expression groups. We found that higher genetically predicted P2rx4 expression was associated with increased post-vapor intake and escalation. In 32 CIE-escalated rats, ivermectin, a positive allosteric modulator of P2X4 receptors, dose-dependently reduced drinking. We stratified rats into three groups: non-responders, mild responders, and high responders. Electrophysiological recordings from CeA slices revealed that ivermectin differentially enhanced GABAergic IPSCs: high-responders exhibited sustained increases in IPSC frequency and selective amplitude reductions, while the two other groups showed transient frequency increases. All groups displayed prolonged rise times, however non-responders showed extended decay times. These findings suggest that P2rx4 upregulation serves as a vulnerability marker for dependence-like behaviors, with ivermectin attenuating withdrawal-driven alcohol consumption by enhancing CeA GABAergic inhibition.
Association of stress-sensitive mid-insula activity with alcohol drinking and negative affect-like behavior during abstinence in mice.
Williams BM, Little JR, Centanni SW
Neuropharmacology · 2026 May · PMID 41690510 · Full text
Stress is central to many neuropsychiatric conditions, including alcohol use disorder (AUD). Stress influences alcohol initiation, escalation, progression to AUD, and relapse. Identifying stress-activated neurocircuits a...
Stress is central to many neuropsychiatric conditions, including alcohol use disorder (AUD). Stress influences alcohol initiation, escalation, progression to AUD, and relapse. Identifying stress-activated neurocircuits and individual variability in these responses is critical for developing new AUD treatment targets. This study investigates the relationship between adult stress response and AUD hyperkatifeia-a prolonged negative emotional state in protracted abstinence. In C57BL/6J mice, repeated restraint stress did not alter ethanol consumption but heightened aversive behavior during abstinence. We examined the mid-insula, a key network hub for emotional regulation and stress response, as a potential mechanism driving this effect. Mid-insula GCaMP activity was higher during active stress-coping behavior, and negatively correlated with ethanol consumption, and positively correlated with GCaMP activity during the novelty-suppressed feeding test in abstinence. Next, we assessed whether stress-induced activity in the stress-sensitive insula-BNST circuit is sufficient to alter ethanol drinking behavior and abstinence-induced avoidance behavior. Chemogenetically inhibiting mid-insula-BNST neurons during stress had sex-specific effects-reducing ethanol consumption in males and abstinence-induced aversive behavior in females. Clustering analysis revealed two distinct phenotypes-one characterized by high active coping during stress, low ethanol consumption, and low avoidance behavior in abstinence, and a second cluster with the opposite pattern. Insula-BNST inhibition during stress shifted female mice toward the former cluster, but had no impact on male cluster identity. Collectively, this study implicates the insula-BNST circuit as a key mediator of stress response, stress-induced drinking, and abstinence-related affective vulnerability, positioning this circuit as a potential biomarker and therapeutic target for hyperkatifeia.
Editorial commentary on Special issue: Ligand bias.
Conibear A, Bailey CP, Kelly E
Neuropharmacology · 2026 May · PMID 41687865 · Publisher ↗
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P2X7 receptors as targets for neuroprotection.
Maneu V, García AG
Neuropharmacology · 2026 May · PMID 41672134 · Publisher ↗
In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic...
In this review we explore the potential of P2X7 receptor blockers to elicit neuroprotection. This conjecture is based on a reasonably well-established role of this receptor in activating glial cells to maintain a chronic low-level neuroinflammatory state in the brain of patients suffering some neurodegenerative diseases (NDDs). In this context we briefly discuss evidence supporting the role of P2X7 receptors (P2X7) in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. From a pathogenic point of view these diseases have specific features but all share a low level neuroinflammatory state with microglia activation and enhanced P2X7 expression. Next, we comment on available P2X7 blockers with central nervous system (CNS) target engagement. Then, we deal with the proof-of-concept concerning the potential of some blockers to mitigate the neuroinflammatory state in preclinical models of the target diseases above mentioned. We follow with a discussion of the scarce number of clinical trials done with some P2X7 blockers in inflammatory diseases. Finally, we discuss the current discrepancy between promising preclinical data and the limited number of clinical trials exploring P2X7 antagonists in NDDs. We provide some clues that may boost clinical trials with single P2X7 blockers but particularly, with their association with other medicines currently being used or that are intended to be prescribed in the treatment of NDDs.
N,N-dimethyltryptamine (DMT) is neither formed nor retained in serotonin terminals in the rat brain.
Palner M, Kolesnik E, Baun C … +2 more , Poetzsch SN, Cumming P
Neuropharmacology · 2026 May · PMID 41672133 · Publisher ↗
Mammalian brain may contain an endogenous pool of the psychedelic substance N,N-dimethyltryptamine (DMT), which may act as a co-transmitter with serotonin (5-HT). We tested the joint hypotheses that endogenous DMT would...
Mammalian brain may contain an endogenous pool of the psychedelic substance N,N-dimethyltryptamine (DMT), which may act as a co-transmitter with serotonin (5-HT). We tested the joint hypotheses that endogenous DMT would accumulate in rat brain after inhibiting monoamine oxidase with pargyline, whereas its acidic metabolite 3-indoleacetic acid (3-IAA) would accumulate after pretreatment with the inhibitor of acidic metabolic transport, probenecid. We also tested the hypothesis that pretreatment with inhibitors of plasma membrane 5-HT uptake (escitalopram, ESC) or the vesicular monoamine transporter 2 (dihydrotetrabenazine, DTBZ) would reduce the retention in brain of exogenous DMT after administration of DMT + harmine (1 mg/kg each). We first established the time courses of brain DMT, 3-IAA, and harmine concentrations for 210 min following DMT + harmine administration. The peak DMT concentration occurred at 45 min and peak 3-IAA levels at 60 min after DMT + harmine administration, with nearly complete washout of exogenous DMT at 210 min. Endogenous DMT levels were below the detection limit of our analytic method, despite pargyline pretreatment, and endogenous 3-IAA was slightly elevated by probenecid treatment, suggesting formation from tryptamine, especially in striatum. ESC did not alter the disposition of exogenous DMT or its metabolite 3-IAA, whereas DTBZ slightly increased 3-IAA formation in some brain regions. In summary, we could not detect an endogenous DMT pool in rat brain, and saw scant evidence of retention of exogenous DMT in 5-HT terminals.
The neuronal P2X7R controversy: Revisiting evidence, methods, and unresolved questions.
Kachappilly N, Pizzo P, Basso E
Neuropharmacology · 2026 May · PMID 41672132 · Publisher ↗
The P2X7 receptor (P2X7R) is an ATP-gated ion channel belonging to the purinergic ligand-gated P2X receptor family. In the central nervous system (CNS), activation of this receptor has been proposed to play a key role in...
The P2X7 receptor (P2X7R) is an ATP-gated ion channel belonging to the purinergic ligand-gated P2X receptor family. In the central nervous system (CNS), activation of this receptor has been proposed to play a key role in the pathogenesis of various neurodegenerative disorders. Its expression has been clearly demonstrated in microglia, where it regulates numerous cellular processes, including cell activation, cytokine release, and calcium signaling. Recent data show convincing arguments for the presence of P2X7R also in other cell types of the nervous system, such as astrocytes, oligodendrocytes, oligodendrocyte progenitor cells (OPCs) and neural progenitor cells (NPCs), although there is still some debate. The most controversial, however, is the presence and role of P2X7R in neurons. In this review, we aim to critically address this question by examining the current literature in the context of the available tools. We revisit the pharmacological regimen required to confirm the functional expression of the receptor and the mouse models that have aided in the investigation of neuronal P2X7R. Finally, we discuss some of the hypothesized contributions of neuronal P2X7R in CNS disorders.
Indole-3-propionic acid inhibits astrocyte inflammation and promotes motor function recovery after spinal cord injury via the AhR/NF-κB/MAPK axis.
Yu D, Kang J, Jiang W … +5 more , Zhang C, Zhao X, Zhao Z, Ning B, Song H
Neuropharmacology · 2026 May · PMID 41663028 · Publisher ↗
Spinal cord injury (SCI) triggers persistent neuroinflammation, primarily driven by aberrant astrocyte activation, which exacerbates secondary neurodegeneration. Indole-3-propionic acid (IPA), a tryptophan-derived metabo...
Spinal cord injury (SCI) triggers persistent neuroinflammation, primarily driven by aberrant astrocyte activation, which exacerbates secondary neurodegeneration. Indole-3-propionic acid (IPA), a tryptophan-derived metabolite produced by the gut microbiota, has recently emerged as a potent anti-inflammatory agent in neurological disorders. However, its therapeutic potential and underlying mechanisms in SCI remain unexplored. In this research, using a TNF-α-stimulated astrocyte model in vitro and a mouse SCI model in vivo, we demonstrated that IPA significantly attenuated the expression of pro-inflammatory mediators (IL-6, IL-1β, iNOS, COX-2, CCL2, CXCL2, CXCL10) in astrocytes, both in vitro and in vivo. Transcriptomic and mechanistic investigations reveal that IPA suppressed NF-κB/MAPK signaling pathways by activating the aryl hydrocarbon receptor (AhR). In SCI mice, IPA treatment reduced glial scar formation, enhanced neuronal survival, and improved long-term motor function, as evidenced by increased BMS scores, inclined plane test performance, and gait coordination. MRI and histopathological analyses further confirmed reduced lesion volume and preserved tissue integrity. Our findings demonstrate that gut microbiota-derived IPA acts through the AhR/NF-κB/MAPK axis to mitigate secondary spinal cord injury by exerting anti-inflammatory and neuroprotective effects. This work not only provides novel pharmacological insights into a metabolite-based approach for SCI treatment but also establishes IPA as a promising endogenous metabolite therapy with high translational potential.
Impact of environmental enrichment on heroin-induced neuroadaptations in the insula, nucleus accumbens and ventral tegmental area.
Galaj E, Vashisht A, Mangal A … +12 more , Barrera E, Nisanov R, Patel N, Sandoval N, Zuniga A, Aminov A, Nachshon Z, Corso E, Fleischer A, Morris C, Shortell H, Ranaldi R
Neuropharmacology · 2026 May · PMID 41651017 · Full text
The ventral tegmental area (VTA), nucleus accumbens (NAc) and insular cortex (IC) are brain regions implicated in addiction. However, the involvement of heroin-induced neuroadaptations in these regions is not fully uncov...
The ventral tegmental area (VTA), nucleus accumbens (NAc) and insular cortex (IC) are brain regions implicated in addiction. However, the involvement of heroin-induced neuroadaptations in these regions is not fully uncovered. Here, we used male and female Long Evans rats to investigate the causal roles of two parallel pathways: VTA→IC and VTA→NAc in opioid-driven behaviors, related neuroadaptations and neural mechanisms by which environmental enrichment (EE) attenuates drug taking and seeking. Our findings are: 1) confirmation that the VTA→IC and VTA→NAc pathways consist of dopamine (DA) and nonDA neurons; 2) demonstration that both pathways are involved in heroin intravenous self-administration (IVSA), reinstatement of heroin seeking and conditioned place preference; 3) dopamine D3 receptor (D3R) mRNA is expressed in the IC, predominantly on glutamate and GABA neurons; 4) dopamine D1 receptors (D1Rs), co-localized with D3Rs, are downregulated in IC and upregulated in NAc following heroin IVSA; 5) Heroin IVSA had no significant effect on D3R and mu opioid receptor (MOR) mRNA expression in these regions; 6) EE reversed heroin-induced neuroadaptations in NAc, but not in IC; 7) heroin-seeking reinstating cues activated cFos in VTA DA and nonDA cells and 8) EE attenuated cue-induced cFos in a manner correlated with the cues' ability to reinstate drug seeking. These results indicate that heroin IVSA causes region-specific, bi-directional neuroadaptations of D1Rs and that EE reverses these neuroadaptations in the NAc. This reversal effect, along with the blunting of drug-cue-induced VTA cFos activation in DA and nonDA cells, might constitute mechanisms by which EE reduces relapse.
Activation of a locus coeruleus to ventral tegmental area noradrenergic pathway blunts binge-like ethanol intake and promotes aversive unconditioned responses in TH-ires-Cre mice.
Drinkuth CR, Dornellas APS, Navarro M … +1 more , Thiele TE
Neuropharmacology · 2026 May · PMID 41638471 · Full text
Ethanol comprises innately aversive properties that may act as a deterrent to overconsumption. We have previously found that chemogenetic activation or inhibition of a noradrenergic locus coeruleus (LC) to rostromedial t...
Ethanol comprises innately aversive properties that may act as a deterrent to overconsumption. We have previously found that chemogenetic activation or inhibition of a noradrenergic locus coeruleus (LC) to rostromedial tegmental nucleus (RMTg) pathway bidirectionally modulates binge-like ethanol intake and aversive reactivity in male and female TH-ires-Cre mice. We previously hypothesized that noradrenergic RMTg circuitry may modulate ethanol intake and aversion through inhibitory inputs to the ventral tegmental area (VTA), a region that is both densely innervated by the RMTg and proposed to coordinate the balance between the rewarding and aversive properties of ethanol. Here, we build upon this work by providing evidence for a direct role of noradrenergic signaling in the VTA in the modulation of binge-like ethanol intake and unconditioned aversive responses. Using "drinking-in-the-dark" procedures, we reveal that site-directed administration of an α-1 adrenergic receptor (AR) agonist into the VTA blunts binge-like ethanol intake and associated blood ethanol concentrations (BECs) without altering sucrose consumption or locomotion. Next, we demonstrate that chemogenetic activation of noradrenergic LC to VTA projection neurons blunts binge-like ethanol intake and BECs in male and female mice without altering sucrose intake or locomotion. Further, we demonstrate that chemogenetic activation of LC to VTA projection neurons induces mid-frequency vocalizations consistent with an aversion- or malaise-like state in mice. The present findings indicate an important involvement of noradrenergic LC to VTA circuitry in the modulation of ethanol intake and aversion.
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