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

Abstract

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 α-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revealed a higher level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (GluA1-Ser831) in the LHb of ethanol-withdrawn rats than that of age-matched naïve counterparts. In ethanol-withdrawn rats, pharmacological inhibition of LHb AMPAR activity significantly mitigated the depressive-like behavior and ethanol drinking and seeking behaviors, but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.

Elevation of Transient Receptor Potential Vanilloid 1 Function in the Lateral Habenula Mediates Aversive Behaviors in Alcohol-withdrawn Rats

“…Accumulating evidence indicates that the lateral habenula (LHb), an epithalamic structure in the brain, plays a crucial role in the aversive behaviors induced by many abused drugs, including alcohol [3][4][5][6][7][8][9] . Recently we demonstrated increased nociception 10,11 , anxiety-and depression-like behaviors 12,13 in alcohol-withdrawn rats. These aberrant behaviors are concomitant with increased activity of, and glutamatergic transmissions to, LHb neurons 12,13 .…”

A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse

“…Increases in LHb neuronal activity are not uniquely correlated with cocaine-induced withdrawal, but are also observed following exposure to ethanol. Withdrawal from ethanol (20% ethanol in a water bottle given intermittently 24 times over 8 weeks) increases spontaneous action potential firing and membrane excitability in LHb neurons measured using ex vivo brain slices (Li et al, 2016 , 2017 ). At the synaptic level, the AMPAR/NMDAR ratio and the frequency of sEPSCs are increased during ethanol withdrawal (Li et al, 2016 , 2017 ).…”

“…Withdrawal from ethanol (20% ethanol in a water bottle given intermittently 24 times over 8 weeks) increases spontaneous action potential firing and membrane excitability in LHb neurons measured using ex vivo brain slices (Li et al, 2016 , 2017 ). At the synaptic level, the AMPAR/NMDAR ratio and the frequency of sEPSCs are increased during ethanol withdrawal (Li et al, 2016 , 2017 ). Additionally, in an ethanol-induced conditioned taste aversion (CTA) paradigm, the basal firing in LHb neurons is increased in vivo when compared to neuronal firing pre-CTA (Tandon et al, 2017 ).…”

Glutamatergic Dysfunction of Lateral Habenula Promotes Depression

“…A recent study identified enhancement of AMPAR and CaMKII activity in LHb in alcohol withdrawal animals from chronic intermittent ethanol consumption with comorbidity of depression [21]. Suppression of AMPAR and CaMKII activity in the LHb improved depressive behavior and alcohol drinking and seeking behaviors.…”

“…Since LHb neurons are almost all glutamatergic [20], GluA1-containing ɑ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), a subtype of ionotropic glutamate receptors, is largely expressed in glutamatergic synapses in LHb, which can be regulated by Ca 2+ /calmodulin-dependent protein II (CaMKII) [21]. AMPAR is composed of four subunits (GluA1-4) and the GluA1 subunit is expressed mostly in the LHb [22].…”