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 67kDa, GAB AA‐αl, and decreased GABA transporter 1. In the same mice, some regulators to GABAergic transmission such as neuregulin l/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. FASEB J. 33, 8614–8622 (2019). http://www.fasebj.org

We recently found that adolescent cocaine exposure (ACE) resulted in an enhancement of the γ‐aminobutyric acid (GABA) neurotransmitter system in the prelimbic cortex (PrL) of adult mice. Here, we aim to further investigate the role of GABAergic transmission, especially parvalbumin (PV) interneurons within PrL in the development of ACE‐induced anxiety‐like behavior, and to assess whether and how electro‐acupuncture (EA) therapeutically manage the ACE‐induced abnormal behaviors in adulthood. ACE mice exhibited the enhanced anxiety‐like behaviors in their adulthood, accompanied by increased GABAergic transmission and PV interneurons in PrL. Chemogenetic blocking PV interneurons in PrL alleviated ACE‐enhanced anxiety‐like behaviors in mice. Importantly, 37‐day EA treatments (mixture of 2 Hz/100 Hz, 1 mA, 30 minutes once a day) at the acupoints of Yintang (GV29) and Baihui (GV20) also alleviated ACE‐induced anxiety‐like behaviors, and rescued ACE‐impaired GABAergic neurotransmitter system and PV interneurons in PrL. In parallel, EA treatments further suppressed the activities of pyramidal neurons in PrL, suggesting that EA treatments seem to perform it beneficial effects on the ACE‐induced abnormal emotional behaviors by “calming down” the whole PrL. Collectively, these findings revealed that hyper‐function of GABAergic transmission, especially mediating by PV interneurons in PrL may be key etiology underlying ACE‐induced anxiety‐like behaviors. At least by normalizing the function of GABAergic and PV interneurons, EA may represent a promising therapeutic strategy for managing adolescent substance use‐related emotional disorders.

We previously found that cocaine abuse could increase micro-RNA134 (miR134) levels in the hippocampus; yet the roles of miR134 in cocaine-related abnormal psychiatric outcomes remain unknown. In this study, using the cocaine-induced conditioned place preference (CPP) mice model, we found that mice exhibit enhanced anxiety-like and depression-like behaviors during the cocaine extinction (CE) period of CPP, accompanied by obviously increased miR134 levels and decreased levels of 19 genes that are associated with synaptic plasticity, glia activity, and neurochemical microenvironments, in the ventral hippocampus (vHP). Knockdown of miR134 in vHP in vivo reversed the changes in 15 of 19 potential gene targets of miR134 and rescued the abnormal anxiety-like and depression-like behavioral outcomes in CE mice. In parallel, knockdown of miR134 reversed CE-induced changes in dendritic spines and synaptic proteins and increased the field excitatory postsynaptic potential (fEPSP) of CA1 pyramidal neurons in the vHP of CE mice. In addition, knockdown of miR134 suppressed the CE-enhanced microglia activity, inflammatory, apoptotic, and oxidative stress statuses in the vHP. With the data taken together, miR134 may be involved in cocaine-associated psychiatric problems, potentially via regulating the expressions of its gene targets that are related to synaptic plasticity and neurochemical microenvironments.

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.

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.