4.8 Article

Reduced motor cortex GABABR function following chronic alcohol exposure

期刊

MOLECULAR PSYCHIATRY
卷 26, 期 2, 页码 383-395

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SPRINGERNATURE
DOI: 10.1038/s41380-020-01009-6

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资金

  1. NSFC [81822017, 81901349, 31771215]
  2. Science and Technology Commission of Shanghai Municipality [18QA1403700, 18JC1420304, 18140901700]
  3. Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20181715]
  4. Hundred-talent Fund from Shanghai Municipal Commission of Health [2018BR21]
  5. Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University [ZH2018ZDA30, ZH2018QNA39]
  6. innovative research team of high-level local universities in Shanghai
  7. Medical Research Council [MR/P008747/1]

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Chronic alcohol exposure leads to significant alterations in cortical GABA(B) receptor function, resulting in weakened cortical inhibition mediated by GABA receptors. These changes may be attributed to the modulation of phosphorylation status of GABA(B) receptor subunits.
The GABA(B) receptor (GABA(B)R) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABA(B)R dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABA(B)R-mediated currents, as well as a decrease of GABA(B1/2)R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABA(B2) subunit, which regulates the surface expression of GABA(B)R. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABA(B)R in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABA(B)R function. The ability to promote GABA(B)R signaling may account for the therapeutic efficacy of baclofen in AUD.

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