Methcathinone,a widely abused synthetic cathinone,poses a significant public health risk because of its severe neurotoxicity and high addictive potential.In this study,we used a zebrafish model to investigate the mech...Methcathinone,a widely abused synthetic cathinone,poses a significant public health risk because of its severe neurotoxicity and high addictive potential.In this study,we used a zebrafish model to investigate the mechanisms underlying its neurobehavioural effects.Methcathinone exposure reduced larval survival and induced a range of abnormal behaviours.Most notably,conditioned place preference(CPP)tests demonstrated the potent rewarding properties of methcathinone,as shown by a significant 22.2%increase in time spent in the drug-paired light zone compared with baseline(P<0.01).Transcriptomic analysis of brain tissue revealed systemic disruption of the neuroactive ligand-receptor interaction pathway.Gene set enrichment analysis(GSEA)further revealed significant suppression ofγ-aminobutyric acid(GABA)signalling(NES=-1.64,P<0.05)and glutamate receptor signalling,including ionotropic and AMPA receptor signalling(P<0.05).Quantitative PCR validation confirmed the marked downregulation of key genes involved in these pathways:the mRNA expression of GABAergic receptors(e.g.,gabra 1 and gabra 2),glutamatergic receptors(e.g.,gria 2 and grin2B),and the dopamine transporter slc6a3 decreased by 67.0%to 97.9%(all P<0.01).These results suggest that methcathinone drives reward-seeking behaviour through a synergistic dual-target mechanism;specifically,the concurrent suppression of GABAergic inhibition and slc6a3-mediated reuptake likely facilitates dopaminergic hyperactivity,whereas the downregulation of glutamate receptors reflects a homeostatic response to overstimulation.Our findings provide novel mechanistic insight into the development of methcathinone use disorder in humans.展开更多
Central respiratory chemoreception is a vital homeostatic mechanism maintaining arterial blood gas levels.Central respiratory chemoreceptors in the retrotrapezoid nucleus(RTN)and nucleus tractus solitarius(NTS)form in...Central respiratory chemoreception is a vital homeostatic mechanism maintaining arterial blood gas levels.Central respiratory chemoreceptors in the retrotrapezoid nucleus(RTN)and nucleus tractus solitarius(NTS)form interconnected circuits to regulate respiratory homeostasis.We hypothesized that NTS GABAergic neurons(NTSGABA)modulate hypercapnic ventilatory responses by targeting ventrolateral medulla Phox2b neurons(VLMPhox2b),particularly Phox2b-expressing RTN neurons.Stimulation of NTSGABA neurons significantly attenuated CO2-evoked ventilatory responses,accompanied by a reduction in CO2-activated Phox2b-expressing RTN neurons.Neural tracing revealed that monosynaptic inputs to the VLMPhox2b neurons primarily originate from the ventrolateral and dorsolateral subdivisions of the NTS.Photostimulation of NTSGABA neurons retrogradely labeled from the VLM markedly suppressed respiratory drive,while chemogenetic activation of these neurons induced hypoventilation,increased spontaneous apnea,and attenuated hypercapnic ventilatory response.These findings demonstrate that activation of the NTS-VLM inhibitory circuit diminishes respiratory motor output,offering novel insights into the regulatory mechanisms of respiratory homeostasis.展开更多
基金Supported by the Natural Science Foundation of Zhejiang Province(No.LTGY23H230001,LGF19H280003)。
摘要Methcathinone,a widely abused synthetic cathinone,poses a significant public health risk because of its severe neurotoxicity and high addictive potential.In this study,we used a zebrafish model to investigate the mechanisms underlying its neurobehavioural effects.Methcathinone exposure reduced larval survival and induced a range of abnormal behaviours.Most notably,conditioned place preference(CPP)tests demonstrated the potent rewarding properties of methcathinone,as shown by a significant 22.2%increase in time spent in the drug-paired light zone compared with baseline(P<0.01).Transcriptomic analysis of brain tissue revealed systemic disruption of the neuroactive ligand-receptor interaction pathway.Gene set enrichment analysis(GSEA)further revealed significant suppression ofγ-aminobutyric acid(GABA)signalling(NES=-1.64,P<0.05)and glutamate receptor signalling,including ionotropic and AMPA receptor signalling(P<0.05).Quantitative PCR validation confirmed the marked downregulation of key genes involved in these pathways:the mRNA expression of GABAergic receptors(e.g.,gabra 1 and gabra 2),glutamatergic receptors(e.g.,gria 2 and grin2B),and the dopamine transporter slc6a3 decreased by 67.0%to 97.9%(all P<0.01).These results suggest that methcathinone drives reward-seeking behaviour through a synergistic dual-target mechanism;specifically,the concurrent suppression of GABAergic inhibition and slc6a3-mediated reuptake likely facilitates dopaminergic hyperactivity,whereas the downregulation of glutamate receptors reflects a homeostatic response to overstimulation.Our findings provide novel mechanistic insight into the development of methcathinone use disorder in humans.
基金supported by grants from the National Natural Science Foundation of China(U23A20431,82000001)Hebei Province Yanzhao Golden Platform Project(HJZD202510)+2 种基金Scientific Technology Research Project of Hebei Province University(BJK2023048)Natural Science Foundation of Hebei Province for Innovative Research Grant Group Project(H2025206897)the Natural Science Foundation of Hebei Province for Precision Medicine Joint Funds(C2020206028).
摘要Central respiratory chemoreception is a vital homeostatic mechanism maintaining arterial blood gas levels.Central respiratory chemoreceptors in the retrotrapezoid nucleus(RTN)and nucleus tractus solitarius(NTS)form interconnected circuits to regulate respiratory homeostasis.We hypothesized that NTS GABAergic neurons(NTSGABA)modulate hypercapnic ventilatory responses by targeting ventrolateral medulla Phox2b neurons(VLMPhox2b),particularly Phox2b-expressing RTN neurons.Stimulation of NTSGABA neurons significantly attenuated CO2-evoked ventilatory responses,accompanied by a reduction in CO2-activated Phox2b-expressing RTN neurons.Neural tracing revealed that monosynaptic inputs to the VLMPhox2b neurons primarily originate from the ventrolateral and dorsolateral subdivisions of the NTS.Photostimulation of NTSGABA neurons retrogradely labeled from the VLM markedly suppressed respiratory drive,while chemogenetic activation of these neurons induced hypoventilation,increased spontaneous apnea,and attenuated hypercapnic ventilatory response.These findings demonstrate that activation of the NTS-VLM inhibitory circuit diminishes respiratory motor output,offering novel insights into the regulatory mechanisms of respiratory homeostasis.