Neuropharmacology最新文献

{"title":"Activation of transient receptor potential vanilloid 4 impairs long-term depression in nucleus accumbens and induces depressive-like behavior","authors":"Kunpeng Li ,&nbsp;Lihan Liu ,&nbsp;Guowen Zhang ,&nbsp;Xiaolin Wang ,&nbsp;Tianchen Gu ,&nbsp;Qi Luo ,&nbsp;Sha Sha ,&nbsp;Yimei Du ,&nbsp;Chunfeng Wu ,&nbsp;Lei Chen","doi":"10.1016/j.neuropharm.2025.110429","DOIUrl":"10.1016/j.neuropharm.2025.110429","url":null,"abstract":"<div><div>Long-term depression (LTD), a form of synaptic plasticity, is impaired in the nucleus accumbens (NAc) in depression. While TRPV4 activation regulates synaptic transmission in the hippocampus, its effects in the NAc remain unclear. Here, we examined the effects of TRPV4 activation on LTD induction in the NAc and depressive-like behavior. Mice that were administered the TRPV4 agonist GSK1016790A into the NAc (GSK-mice) showed depressive-like behavior and impaired LTD induction in NAc slices. Additionally, the mRNA and protein levels of dopamine D2 receptor (D2R) and A-type gamma-aminobutyric acid receptor (GABA_AR) were markedly decreased in the NAc of GSK-mice. Meanwhile, administering a D2R (quinpirole) or GABA_AR (muscimol) agonist reversed LTD impairment in the NAc. The protein levels of phosphorylated protein kinase C (p-PKC) increased markedly and that of phosphorylated protein kinase B (p-Akt) decreased in the NAc of GSK mice. Administration of a PKC antagonist (GF109203X) or phosphatidylinositol 3-kinase (PI3K) agonist (740 Y-P) significantly increased GABA_AR protein levels and restored LTD induction in the NAc of GSK-mice. Administration of quinpirole increased p-Akt and GABA_AR protein levels in the NAc of GSK-mice. Finally, administration of quinpirole, muscimol, GF109203X or 740 Y-P improved the depressive-like behavior in GSK-mice. This study suggests that activation of TRPV4 impairs LTD induction in the NAc and induces depressive-like behavior, which is likely mediated by down-regulating D2R to inhibit PI3K-Akt pathway, and activating PKC to decrease the expression of GABA_AR.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110429"},"PeriodicalIF":4.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724544","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}

{"title":"Chronic social stress induces generalized hyper-sensitivity to aversion: A mouse model with translational validity for understanding and treating negative valence disorders","authors":"Giulia Poggi ,&nbsp;Adrián Portalés ,&nbsp;Mélisse Robert ,&nbsp;Céline Hofer ,&nbsp;Sophie Schmid ,&nbsp;Diana Kúkeľová ,&nbsp;Hannes Sigrist ,&nbsp;Stefan Just ,&nbsp;Bastian Hengerer ,&nbsp;Christopher R. Pryce","doi":"10.1016/j.neuropharm.2025.110430","DOIUrl":"10.1016/j.neuropharm.2025.110430","url":null,"abstract":"<div><div>The RDoC framework focuses on neurobehavioral processes often dysfunctional in mental disorders and commensurate with translational research. Generalized hyper-sensitivity to aversion/threat is common in various stress-related emotional disorders; increased Pavlovian aversion learning-memory (PAL, PAM) provides a translational paradigm for its study. Here we present the development and application of a mouse model for the study of generalized hyper-sensitivity to aversion/threat. In male adult mice, chronic exposure to social aversion (chronic social stress, CSS) leads, relative to controls (CON), to increased acquisition and expression of tone-footshock conditioned freezing behavior. The altered neurobehavioral state of CSS mice is expected to involve structure-function changes in amygdala: in CSS mice, higher levels of both PAL and PAM freezing behavior co-occurred with fewer lateral/basal amygdala glutamate neurons expressing the immediate early-gene protein c-Fos. A current antidepressant, SSRI escitalopram, reversed excessive PAM freezing behavior in CSS mice with sub-chronic dosing. The model was applied to investigate 3 compounds with novel mechanisms of action: indoleamine dioxygenase 1 (IDO 1) inhibition, somatostatin receptor 4 (SSTR4) agonism, and transient receptor potential canonical channels 4 and 5 (TRPC4/5) inhibition. For each, there was evidence for attenuation of excessive PAL and/or PAM in CSS mice. Preclinical validation of TRPC4/5 channels inhibition contributed to the decision to investigate, and accurately predicted, clinical efficacy, measured as reduced amygdala and emotional reactivities to aversion in major depressive disorder. Future work will focus on (back-)translational studies that address stress-induced changes in amygdala reactivity and aversion processing, their underlying etio-pathophysiological causes, and neuropharmacological responsiveness.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110430"},"PeriodicalIF":4.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724545","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}

{"title":"A novel selective phosphodiesterase 9 inhibitor, irsenontrine (E2027), enhances GluA1 phosphorylation in neurons and improves learning and memory via cyclic GMP elevation","authors":"Yasuharu Ishihara ,&nbsp;Mai Ando ,&nbsp;Yasuaki Goto ,&nbsp;Sadaharu Kotani ,&nbsp;Naoto Watanabe ,&nbsp;Yosuke Nakatani ,&nbsp;Satoko Ishii ,&nbsp;Norimasa Miyamoto ,&nbsp;Yuji Mano ,&nbsp;Yukio Ishikawa","doi":"10.1016/j.neuropharm.2025.110428","DOIUrl":"10.1016/j.neuropharm.2025.110428","url":null,"abstract":"<div><div>Phosphodiesterase 9 (PDE9) plays a critical role in synaptic plasticity and cognitive function by modulating cyclic GMP (cGMP). Many reports have shown that PDE9 inhibition improves cognitive function and synaptic plasticity in rodents. Several studies have found that the NO/cGMP/PKG pathway is downregulated in patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) and in older individuals. A PDE9 inhibitor could therefore be a potential therapeutic approach for improving cognitive dysfunction in dementia, including in AD and DLB. We previously discovered a novel PDE9 inhibitor, irsenontrine (E2027). In the current study, irsenontrine showed highly selective affinity for PDE9 with more than 1800-fold selectivity over other PDEs. Irsenontrine maleate significantly increased intracellular cGMP levels in rat cortical primary neurons, and phosphorylation of AMPA receptor subunit GluA1 was induced following cGMP elevation. Oral administration of irsenontrine significantly upregulated cGMP levels in the hippocampus and cerebrospinal fluid (CSF) of naïve rats, and a novel object recognition test showed that irsenontrine administration also significantly improved learning and memory. The effects of irsenontrine were confirmed in rats treated with Nω-nitro-<span>l</span>-arginine methyl ester hydrochloride (<span>l</span>-NAME), a model of learning and memory impairment due to downregulation of the cGMP pathway. <span>l</span>-NAME downregulated cGMP in the CSF and hippocampus and impaired novel object recognition, but oral administration of irsenontrine clearly attenuated these phenotypes. These results indicate that irsenontrine improves learning and memory via the elevation of cGMP levels, and they strongly suggest that irsenontrine could be a novel therapeutic approach against cognitive dysfunction.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110428"},"PeriodicalIF":4.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730778","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}

{"title":"Chronic stress-related behavioral and synaptic changes require caspase-3 activation in the ventral hippocampus of male mice","authors":"Huiyoung Kwon ,&nbsp;Jieun Jeon ,&nbsp;Eunbi Cho ,&nbsp;Somin Moon ,&nbsp;A Young Park ,&nbsp;Hyun Ji Kwon ,&nbsp;Kyoung Ja Kwon ,&nbsp;Jong Hoon Ryu ,&nbsp;Chan Young Shin ,&nbsp;Jee Hyun Yi ,&nbsp;Dong Hyun Kim","doi":"10.1016/j.neuropharm.2025.110431","DOIUrl":"10.1016/j.neuropharm.2025.110431","url":null,"abstract":"<div><div>Although numerous studies have suggested that chronic stress is a major risk factor for major depressive disorder, the process by which stress causes depression is still not fully understood. Previously, we investigated glucocorticoids, which are stress response hormones that activate a synapse-weakening pathway. Therefore, we hypothesized that chronic stress may cause synaptic depression, which could reduce excitability related to emotions. Animals underwent chronic restraint stress (CRS), followed by basal synaptic transmission measurement in hippocampal slices to assess synaptic function. Drugs were infused into the ventral hippocampus via cannulation before behavioral tests, including forced swimming, tail suspension, and sucrose intake tests, which evaluated depressive-like behaviors and anhedonia. The field excitatory postsynaptic potentials (fEPSPs) are reduced by chronic restraint stress (CRS) in the ventral hippocampus. The ventral hippocampi of mice treated with CRS showed low levels of fEPSP after the forced swim test (FST). In the FST and tail suspension test, CRS-induced increases in immobility time were prevented by the acute inhibition of AMPAR internalization by Tat-GluA2_3y, which also prevented fEPSP reduction. Mice lacking caspase-3 exhibited resilience to CRS-induced increases in immobility time in the FST, as well as changes in the functionality of synaptic AMPAR. Finally, the caspase-3 inhibitor Z-DEVD-FMK rapidly blocked the CRS-induced increase in immobility time in the FST and the CRS-induced decrease in sucrose preference. These findings suggest that chronic stress-related behavioral changes may require caspase-3-dependent alterations in ventral hippocampal synapses.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110431"},"PeriodicalIF":4.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715662","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}

{"title":"Activated mTORC1 signaling pathway aggravates cisplatin induced oxidative damage by inhibiting autophagy in mouse cochlear hair cells","authors":"Na-Na Xu ,&nbsp;Yin-Chuan Wen ,&nbsp;Jing Pan ,&nbsp;Fan Shu ,&nbsp;Jia-xi Qu ,&nbsp;Xiao-Fei Qi ,&nbsp;Jie Tang","doi":"10.1016/j.neuropharm.2025.110433","DOIUrl":"10.1016/j.neuropharm.2025.110433","url":null,"abstract":"<div><div>Platinum-based antitumor drugs, such as cisplatin and carboplatin, are well-known for their severe ototoxicity. The ototoxic effects of these drugs are primarily attributed to oxidative stress induced damage within cochlear hair cells (HCs), leading to cell death and subsequent irreversible hearing loss. Over the past decade, studies have demonstrated that upregulating autophagy levels in HCs can greatly alleviate the death of cochlear HCs as part of the oxidative damage induced by ototoxic drugs. However, the molecular mechanisms by which platinum-based drugs affect autophagy and ultimately lead to HCs death remain unclear. In the present study, we investigated the effects of cisplatin on the mTOR signaling pathway, a critical regulator of autophagy, in cochlear explants of mice. Our results indicated that while cisplatin enhances autophagy activity initially, it also activates mTOR Complex1 (mTORC1) within HCs. The persistent activation of mTORC1 inhibits autophagy in HCs, resulting in the accumulation of reactive oxygen species and leading to cell death. Further pharmacological experiments confirmed the protective role of rapamycin, a specific mTORC1 inhibitor, highlighting the importance of autophagy in combating cisplatin-induced ototoxicity. Our findings suggest that modulating the mTOR signaling pathway to regulate autophagy could be an effective strategy for preventing cisplatin-induced ototoxic damage.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110433"},"PeriodicalIF":4.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715139","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}

{"title":"Tabersonine ameliorates depressive-like behavior by inhibiting NLRP3 inflammasome activation in a mouse model","authors":"Yan Shi ,&nbsp;Yue Hu ,&nbsp;Yaoxue Gan ,&nbsp;Zhaoyu Mi ,&nbsp;Shuting Luo ,&nbsp;Jia Lei ,&nbsp;Qian Fang ,&nbsp;Haoyu Li","doi":"10.1016/j.neuropharm.2025.110432","DOIUrl":"10.1016/j.neuropharm.2025.110432","url":null,"abstract":"<div><div>Depression, a common mental disorder, is intimately linked to neuroinflammation. In the central nervous system, microglia, the principal cells involved in immunity, are crucial in neuroinflammation and closely associated with the pathogenesis of depression. Several studies have demonstrated that depressive-like behaviors could be ameliorated by improving brain inflammation. Notably, natural products occupy a critical position in the study of antidepressants. Herein, we explored the antidepressant effects of tabersonine (Tab), a natural inhibitor of NLRP3. Tab significantly improved depressive-like behaviors and anxiety in lipopolysaccharide (LPS)-treated mice. To further elucidate mechanisms underlying the antidepressant actions of Tab, BV2 microglial cells were exposed to LPS and ATP in vitro. Tab effectively inhibited NLRP3 inflammasome activation, subsequent Caspase-1 cleavage, and interleukin-1β secretion both in the hippocampi of mice in vivo and BV2 cells in vitro. Additionally, Tab strongly decreased the concentrations of the proinflammatory cytokines interleukin-1β, tumor necrosis factor, and interleukin-6 in BV2 cell culture supernatants and sera of mice. Further studies indicated that Tab improved LPS-induced neuronal loss, as indicated by a significant rise in the quantity of Nissl-positive cells within the hippocampal regions CA1, CA3, and dentate gyrus. Importantly, Tab counteracted the LPS-induced microglial activation in the hippocampus. Our results indicate that Tab significantly improves LPS-triggered depressive-like behaviors and reverses injuries to hippocampal microglia and neurons, implying its potential as a therapeutic agent for depression.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"273 ","pages":"Article 110432"},"PeriodicalIF":4.6,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730900","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}

{"title":"Modulation of mu-opioid receptor function alters electroshock seizure responses in mice","authors":"Thomas N. Ferraro ,&nbsp;James R. DeChiara ,&nbsp;Ruoyu Chen ,&nbsp;Yong Chen ,&nbsp;Glenn A. Doyle ,&nbsp;Russell J. Buono","doi":"10.1016/j.neuropharm.2025.110427","DOIUrl":"10.1016/j.neuropharm.2025.110427","url":null,"abstract":"<div><div>We studied the effects of mu-opioid receptor (MOR) modulation on seizure responses to electroshock stimulation in C57BL/6J (B6) and DBA/2J (D2) mice of both sexes. Using a genetic approach, we show that B6 and D2 mice with a constitutive deletion of the MOR gene <em>Oprm1</em> have a significantly reduced maximal electroconvulsive shock (ECS) seizure threshold. Using a pharmacological approach, we show that morphine treatment (25 mg pellet, s.c.) significantly reduces expression of maximal ECS seizures in both wild type strains, and conversely, that naltrexone treatment (1–10 mg/kg, s.c.) increases maximal ECS seizure susceptibility, more so in B6 mice than in D2. Unexpectedly, we observe that higher doses of naltrexone (100–500 mg/kg, i.p.) elicit generalized seizures, with D2 mice displaying significantly greater susceptibility than B6. Together, results suggest that decreasing MOR function increases ECS seizure susceptibility in mice, whereas increasing MOR function decreases ECS seizure susceptibility. The greater sensitivity of D2 mice to the direct proconvulsant effect of high dose naltrexone is consistent with the relative response of this strain to other chemoconvulsants and suggests that endogenous opioids play a role in mediating the previously reported robust difference in seizure susceptibility between D2 and B6 mice. On the other hand, our finding that naltrexone intensifies ECS seizures more in B6 mice than D2 underscores the complex nature of seizure susceptibility and the interaction between opioids and seizures. We conclude that further refinement of approaches to modulate neuronal signaling linked to the effect of the MOR on electroshock seizure responses may provide clues for development of new anti-epilepsy treatments.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110427"},"PeriodicalIF":4.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692798","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}

{"title":"Discriminative stimulus and antinociceptive effects of sixteen nitazene analogs in rodents","authors":"Michael B. Gatch,&nbsp;R. Darbi Hill,&nbsp;Megana Sundar,&nbsp;Ritu A. Shetty","doi":"10.1016/j.neuropharm.2025.110416","DOIUrl":"10.1016/j.neuropharm.2025.110416","url":null,"abstract":"<div><div>Analogs of the benzimidazole opioid compound, etonitazene, have appeared in the illicit drug market in an attempt to circumvent control of fentanyl analogs. This study examined behavioral effects of 16 nitazene analogs. The discriminative stimulus effects of morphine, fentanyl, butonitazene, clonitazene, N-desethyl isotonitazene, etonitazene, etodesnitazene, 5-methyl etodesnitazene, 5-aminoisotonitazene, isotodesnitazene, isotonitazene, N-piperydinyl etonitazene, N-piperidinyl isotonitazene, N-pyrrolidino etonitazene, N-pyrrolidino isotonitazene, N-pyrrolidino metonitazene, N-pyrrolidino protonitazene, and ethyleneoxynitazene were tested in male Sprague-Dawley rats trained to discriminate morphine from saline. Antinociception was tested using a warm-water tail-flick assay using male Swiss-Webster mice. All the nitazene test compounds fully substituted for the discriminative stimulus effects of morphine and the substitution was blocked by naltrexone. The potencies of the test compounds varied widely with five compounds being 3- to 5-fold more potent than fentanyl (ED₅₀ = 0.009 mg/kg), two compounds being roughly equipotent, and nine compounds being 2- to 170-fold less potent.</div><div>Similarly, all of nitazene test compounds produced full antinociceptive effects at 50 °C that were blocked by naltrexone. Seven compounds were 7- to 150-fold more potent than fentanyl (ED₅₀ = 0.058 mg/kg), four compounds were approximately equipotent, and five compounds were less 3- to 20-fold less potent. Antinociceptive time courses varied widely, with the duration of peak effects ranging from 15 to 90 min. All benzimidazole analogs tested produced opioid-like effects with a wide range of potencies and time courses. These compounds will likely have substantial liability for illicit use, whether on their own or as contaminants.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110416"},"PeriodicalIF":4.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692780","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}

{"title":"Artesunate demonstrates neuroprotective effect through activation of lysosomal function and inhibition of cGAS-STING pathway","authors":"Hongqiao Wei ,&nbsp;Yongxin Chen ,&nbsp;Zhenmin Qin ,&nbsp;Honglei Wang ,&nbsp;Yujia Liu ,&nbsp;Tang Song ,&nbsp;Yong Wu ,&nbsp;Wanxiang Hu ,&nbsp;Xiaowei Huang ,&nbsp;Guodong Lu ,&nbsp;Jing Zhou","doi":"10.1016/j.neuropharm.2025.110426","DOIUrl":"10.1016/j.neuropharm.2025.110426","url":null,"abstract":"<div><div>Artesunate, a derivative of artemisinin, has a variety of pharmacological effects. Its potential application in ischemic brain injury still largely unknown. This study investigated the therapeutic effect and pharmacological mechanism of artesunate in neuronal injury following cerebral ischemia, and explore the potential role of lysosomal function and cGAS-STING signaling pathway in ischemia injury and artesunate treatment. Studies in rat models have revealed that artesunate can ameliorate neuronal injury and improve learning and memory function following ischemic insults. Furthermore, both <em>in vivo</em> and <em>in vitro</em> studies have confirmed that artesunate can protect neural cells from ischemic injury-induced cell death. Mechanistically, artesunate appears to exert its neuroprotective actions by activating lysosomal function and inhibiting the cGAS-STING pathway-mediated inflammatory response. Our findings provide valuable insights into the therapeutic effects of artesunate exerting a neuroprotective role in chronic ischemic brain injury by activating lysosomal function, inhibiting the cGAS-STING pathway, and regulating the inflammatory response. This study offers a potential therapeutic strategy by regulating lysosome for the treatment of stroke and related neurological disorders.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110426"},"PeriodicalIF":4.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674333","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}

{"title":"Unveiling the potential abuse liability of α-D2PV: A novel α-carbon phenyl-substituted synthetic cathinone","authors":"Núria Nadal-Gratacós ,&nbsp;Sandra Mata ,&nbsp;Pol Puigseslloses ,&nbsp;Morgane De Macedo ,&nbsp;Virginie Lardeux ,&nbsp;Stephanie Pain ,&nbsp;Fu-Hua Wang ,&nbsp;Liselott Källsten ,&nbsp;David Pubill ,&nbsp;Xavier Berzosa ,&nbsp;Jan Kehr ,&nbsp;Marcello Solinas ,&nbsp;Jordi Camarasa ,&nbsp;Elena Escubedo ,&nbsp;Raul López-Arnau","doi":"10.1016/j.neuropharm.2025.110425","DOIUrl":"10.1016/j.neuropharm.2025.110425","url":null,"abstract":"<div><div>Synthetic cathinones are emerging psychoactive substances designed to mimic the effects of classical psychostimulants. Among them, α-D2PV, a novel pyrrolidine-containing cathinone characterized by a phenyl group on the α-carbon atom, has gained significant attention. This study investigates the <em>in vitro</em> and <em>in silico</em> mechanism of action as well as the abuse liability of α-D2PV using rodent models. Dopamine (DA), noradrenaline (NE), and serotonin (5-HT) uptake inhibition assays were conducted in HEK293 cells expressing the corresponding human monoamine transporter, complemented by molecular docking studies at the DA transporter (DAT). Behavioral studies in male Swiss CD-1 mice assessed locomotor activity and conditioned place preference, while microdialysis and self-administration experiments were performed in male Sprague-Dawley rats. The findings reveal that α-D2PV is a potent DA and NE uptake inhibitor, with minimal activity at the 5-HT transporter (SERT). Docking studies showed that the benzene rings of α-PVP and α-D2PV align precisely in their most stable conformations at DAT. In vivo, α-D2PV elicited dose-dependent hyperlocomotion, thigmotaxis, and rewarding effects in mice, alongside increased extracellular DA levels in the nucleus accumbens of awake rats. Self-administration experiments confirmed α-D2PV's high reinforcing efficacy, indicating a significant risk of abuse in humans. Finally, these results underscore the necessity for continued surveillance of α-D2PV within the illicit drug market. Furthermore, novel synthetic cathinones incorporating a phenyl ring at the α-carbon side chain warrant proactive monitoring due to their potential to retain dopaminergic activity and evade initial legal controls.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"272 ","pages":"Article 110425"},"PeriodicalIF":4.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674307","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}