Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats

&NA; Depression is a well‐known risk factor for developing relapse drinking, but the neuronal mechanisms underlying the interactions between depression and alcohol use disorders remain elusive. Accumulating evidence has associated depression with hyperactivity of the lateral habenula (LHb), an epithalamic structure in the brain that encodes aversive signals. Glutamate receptors contribute substantially to the excitability of LHb neurons. Glutamatergic synapses in LHb neurons largely express GluA1‐containing &agr;‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) that can be modulated by Ca2+/calmodulin‐dependent protein II (CaMKII). In the current study, we tested the hypothesis that withdrawal from repeated cycles of ethanol drinking triggers an increase in LHb AMPAR and CaMKII activity concomitant with depression‐like symptoms, and their inhibitions bring a reduction in depressive‐like behaviors and alcohol consumption. Western blotting revealed a higher level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (GluA1‐Ser831) in the LHb of ethanol‐withdrawn rats than that of age‐matched naïve counterparts. In ethanol‐withdrawn rats, pharmacological inhibition of LHb AMPAR activity significantly mitigated the depressive‐like behavior and ethanol drinking and seeking behaviors, but affected neither sucrose intake nor locomotor activity; and inhibition of LHb CaMKII activity, or chemogenetic inhibition of LHb activity produced similar effects. Conversely, activation of LHb AMPARs induced depressive‐like behaviors in ethanol‐naïve rats. These results demonstrate that CaMKII‐AMPAR signaling in the LHb exemplifies a molecular basis for depressive‐like symptoms during ethanol withdrawal and that inhibition of this signaling pathway may offer a new therapeutic approach to address the comorbidity of alcohol abuse and depression. Graphical abstract Figure. No caption available. HighlightsDepressive‐like behavior is observed in ethanol‐withdrawn rats.Excitability of LHb neurons is increased in withdrawn rats.Phosphorylated AMPAR and CaMKII activity is increased in the LHb of withdrawn rats.Inhibition of LHb AMPAR, CaMKII, and neurons rescues depressive‐like behavior.Inhibition of LHb AMPAR, CaMKII, and neurons reduces ethanol intake.

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