Abstract：
:The GABAB receptor (GABABR) 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 GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R 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 GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.
journal_name
Mol Psychiatryjournal_title
Molecular psychiatryauthors
Peng SY,Shi Z,Zhou DS,Wang XY,Li XX,Liu XL,Wang WD,Lin GN,Pan BX,Voon V,Grace AA,Heilig M,Wong ML,Yuan TFdoi
10.1038/s41380-020-01009-6subject
Has Abstractpub_date
2021-01-11 00:00:00eissn
1359-4184issn
1476-5578pii
10.1038/s41380-020-01009-6pub_type
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