RESUMEN
Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.
Asunto(s)
Astrocitos , Trastornos de la Memoria , Metanfetamina , Microglía , Minociclina , Memoria Espacial , Animales , Metanfetamina/toxicidad , Microglía/efectos de los fármacos , Microglía/metabolismo , Ratones , Trastornos de la Memoria/inducido químicamente , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Memoria Espacial/fisiología , Memoria Espacial/efectos de los fármacos , Masculino , Minociclina/farmacología , Ratones Endogámicos C57BL , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/patología , Estimulantes del Sistema Nervioso Central/toxicidadRESUMEN
Methamphetamine (METH) elicits endogenous glutamate (Glu) in the brain, which could partially explain METH-induced memory deficits. Here, we investigated the therapeutic effects of electroacupuncture (EA) on spatial memory deficits in METH withdrawal mice and its potential synaptic mechanisms. We found that EA at acupoints 'Baihui' and 'Yintang' ameliorated the impaired spatial memory in METH withdrawal mice. In parallel, EA attenuated the Glu levels in vivo and suppressed the neuronal activities within dCA1 of METH withdrawal mice, as indicated by the decreasing c-Fos levels and the amplitude of mEPSP. In the dCA1, EA decreased A1-like astrocytes but increased astrocytic glutamatergic transporting molecules including glutamate transporter 1 and glutamine synthase. However, EA seemed to have no effects on presynaptic Glu transmission from the dCA3, as evidenced by the similiar levels of c-Fos in the dCA3 neurons, synaptic vesicular markers of dCA3 neural terminals and values of paired-pulse ratio in the dCA1 neurons between EA-treated and sham EA-treated METH withdrawal mice. These findings suggest that EA might normalize the dCA1 Glu levels at least in part through enhancing astrocyte-mediated Glu clearance. Taken together, astrocytes might be a novel target for developing therapeutic interventions against the impaired memory behaviours in METH users, and EA represents a promising non-invasive therapeutic strategy for the management of drug-caused memory deficits.
Asunto(s)
Trastornos Relacionados con Anfetaminas/fisiopatología , Astrocitos/efectos de los fármacos , Electroacupuntura/métodos , Ácido Glutámico/efectos de los fármacos , Trastornos de la Memoria/terapia , Memoria Espacial/efectos de los fármacos , Animales , Masculino , Metanfetamina/farmacología , Ratones , Neuronas/efectos de los fármacosRESUMEN
Methamphetamine (METH) is a common abused drug. METH-triggered glutamate (Glu) levels in dorsal CA1 (dCA1) could partially explain the etiology of METH-caused abnormal memory, but the synaptic mechanism remains unclear. Here, we found that METH withdrawal disrupted spatial memory in mice, accompanied by the increases in Glu levels and postsynaptic neuronal activities at dCA1 synapses. METH withdrawal weakened the capacity of Glu clearance in astrocytes, as indicated by increasing the A1-like astrocytes and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), decreasing the Glu transporter 1(GLT-1, also known as EAAT2 or SLC1A2), Glu-aspartate-transporter (GLAST also known as EAAT1 or SLC1A3) and astrocytic glutamine synthase (GS), but failed to affect the presynaptic Glu release from dCA3 within dCA1. Moreover, we identified that in vitro A1-like astrocytes exhibited an increased STAT3 activation and the impaired capacity of Glu clearance. Most importantly, selective knockdown of astrocytic STAT3 in vivo in dCA1 restored the astrocytic capacity of Glu clearance, normalized Glu levels at dCA1 synapses, and finally rescued METH withdrawal-disrupted spatial memory in mice. Thus, astrocytic Glu clearance system, especially STAT3, serves as a novel target for future therapies against METH neurotoxicity.
Asunto(s)
Astrocitos , Metanfetamina , Animales , Astrocitos/fisiología , Transportador 2 de Aminoácidos Excitadores/genética , Ácido Glutámico , Metanfetamina/toxicidad , Ratones , Factor de Transcripción STAT3/genética , Memoria EspacialRESUMEN
We have recently shown in rats that adolescent cocaine exposure induces prolonged modifications on synapses in medial prefrontal cortex (mPFC), which might contribute to long-term behavioral outcomes in adulthood. In this study, we further investigated the molecular mechanisms underlying adolescent cocaine exposure-related psychiatric problems in adulthood, especially focusing on the alterations of GABAergic transmission in prelimbic cortex (PrL), 1 subregion of mPFC. Consistent with a previous study, adolescent cocaine-exposed mice exhibited enhanced anxiety-like behaviors in their adulthood. In the same mice models, depression-like behaviors increased as well, but the conditioned place preference formed normally. In parallel, activities of pyramidal neurons at layer V of PrL were reduced after adolescent cocaine exposure, accompanied by an increase in the percentage of symmetric synapses in PrL of adult mice. Additionally, miniature inhibitory postsynaptic currents rather than miniature excitatory postsynaptic currents were increased on these pyramidal neurons, and increased levels of GABA were found in adult PrL. The molecules in the GABAergic system in adult PrL were also changed by adolescent cocaine use, as indicated by increased glutamate decarboxylase 67 kDa, GABAA-α1, and decreased GABA transporter 1. In the same mice, some regulators to GABAergic transmission such as neuregulin 1/ErbB4 signals were heightened as well. Collectively, these findings revealed that adolescent cocaine exposure results in permanent enhancement of GABAergic transmission on pyramidal neurons in PrL, which subsequently attenuate the activities of these neurons and ultimately contributes to the development of psychiatric disorders in later life.-Shi, P., Nie, J., Liu, H., Li, Y., Lu, X., Shen, X., Ge, F., Yuan, T.-F., Guan, X. Adolescent cocaine exposure enhances the GABAergic transmission in the prelimbic cortex of adult mice.
Asunto(s)
Cocaína/efectos adversos , Corteza Prefrontal/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Receptores de GABA-A/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Células Piramidales/metabolismo , Sinapsis/metabolismoRESUMEN
The CaO dissolution from slag, as well as the effects of influencing parameters (i.e. pH and Ca2+ concentration) on the ammonium adsorption onto zeolite, was systematically studied in this paper. Modeling results of Ca2+ and OH- release from slag indicated that pseudo-second-order reaction had a better fitness than pseudo-first-order reaction. Changing pH value from 7 to 12 resulted in a drastic reduction of the ammonium adsorption capacity on zeolite, from the peak adsorption capacity at pH 7. High Ca2+ concentration in solution also inhibited the adsorption of ammonium onto zeolite. There are two proposed mechanisms for steel slag inhibiting the ammonium adsorption capacity of zeolite. On the one hand, OH- released from steel slag can react with ammonium ions to produce the molecular form of ammonia (NH3·H2O), which would cause the dissociation of NH4+ from zeolite. On the other hand, Ca2+ could replace the NH4+ ions to adhere onto the surface of zeolite. An innovative substrate filling configuration with zeolite placed upstream of the steel slag was then proposed to eliminate the disadvantageous effects of steel slag. Experimental results showed that this novel filling configuration was superior to two other filling configurations in terms of ammonium removal.
Asunto(s)
Acero/química , Contaminantes Químicos del Agua/química , Humedales , Zeolitas/química , Adsorción , Compuestos de Amonio , Purificación del AguaRESUMEN
BACKGROUND: Anxiety is a prominent withdrawal symptom of methamphetamine (Meth) addiction. Recently, the gut microbiota has been regarded as a promising target for modulating anxiety. Gegen-Qinlian decoction (GQD) is a classical Traditional Chinese Medicine applied in interventions of various gut disorders by balancing the gut microbiome. We aim to investigate whether GQD could alleviate Meth withdrawal anxiety through balancing gut microbiota and gut microenvironment. METHODS: Meth withdrawal anxiety models were established in mice. GQD were intragastric administrated into Meth-withdrawn mice and controls. Gut permeability and inflammatory status were examined in mice. Germ-free (GF) and antibiotics-treated (Abx) mice were used to evaluate the role of gut bacteria in withdrawal anxiety. Gut microbiota was profiled with 16s rRNA sequencing in feces. Metabolomics in colon tissue and in Akkermansia culture medium were performed. RESULTS: Meth withdrawal enhanced anxiety-like behaviors in wild-type mice, and altered gut permeability, and inflammatory status, while GQD treatment during the withdrawal period efficiently alleviated anxiety-like behaviors and improved gut microenvironment. Next, we found Germ-free (GF) and antibiotics-treated (Abx) mice did not develop anxiety-like behaviors by Meth withdrawal, indicating the essential role of gut bacteria in Meth withdrawal induced anxiety. Then, it was observed that gut microbiota was greatly affected in Meth-withdrawn mice, especially the reduction in Akkermansia. GQD can rescue the gut microbiota and reverse Akkermansia abundance in Meth-withdrawn mice. Meanwhile, GQD can also restore the Meth-impaired Akkermansia growth in vitro. Further, GQD restored several common metabolite levels both in colon in vivo and in Akkermansia in vitro. CONCLUSIONS: We revealed a novel effect of GQD on Meth withdrawal anxiety and identified its pharmacological target axis as "Akkermansia-Akkermansia metabolites-gut metabolites-gut microenvironment". Our findings indicated that targeting gut bacteria with TCM, such as GQD, might be a promising therapeutic strategy for addiction and related withdrawal symptoms.