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Ketamine normalizes binge drinking‐induced defects in glutamatergic synaptic transmission and ethanol drinking behavior in female but not male mice

Nicole A. Crowley,Sarah N. Magee,Mengyang Feng,S. Jefferson,Christian J Morris,Nigel C. Dao,Dakota Brockway,B. Luscher

Published 2019 in Neuropharmacology

ABSTRACT

&NA; Ketamine is a fast acting experimental antidepressant with significant therapeutic potential for emotional disorders such as major depressive disorder and alcohol use disorders. Of particular interest is binge alcohol use, which during intermittent withdrawal from drinking involves depressive‐like symptoms reminiscent of major depressive disorder. Binge drinking has been successfully modeled in mice with the Drinking in the Dark (DID) paradigm, which involves daily access to 20% ethanol, for a limited duration and selectively during the dark phase of the circadian light cycle. Here we demonstrate that DID exposure reduces the cell surface expression of NMDA‐ and AMPA‐type glutamate receptors in the prelimbic cortex (PLC) of female but not male mice, along with reduced activity of the mammalian target of rapamycin (mTOR) signaling pathway. Pretreatment with an acute subanesthetic dose of ketamine suppresses binge‐like ethanol consumption in female but not male mice. Lastly, DID‐exposure reduces spontaneous glutamatergic synaptic transmission in the PLC of both sexes, but synaptic transmission is rescued by ketamine selectively in female mice. Thus, ketamine may have therapeutic potential as an ethanol binge suppressing agent selectively in female subjects. HighlightsDrinking in the Dark reduces glutamatergic synaptic transmission and mTOR signaling in the medial prefrontal cortex.Ketamine prophylactically reduces binge‐like ethanol consumption in female, but not male mice.Ketamine‐induced normalization of glutamatergic synaptic transmission reverses excessive alcohol drinking.

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