Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula

Abstract

Alcohol use disorders (AUDs) and anxiety disorders (ADs) are often seen concurrently, but their underlying cellular basis is unclear. For unclear reasons, the lateral habenula (LHb), a key brain region involved in the pathophysiology of ADs, becomes hyperactive after ethanol withdrawal. M-type K channels (M-channels), important regulators of neuronal activity, are abundant in the LHb, yet little is known about their role in AUDs and associated ADs. We report here that in rats at 24 h withdrawal from systemic ethanol administration (either by intraperitoneal injection, 2 g/kg, twice/day, for 7 days; or intermittent drinking 20% ethanol in a two-bottle free choice protocol for 8 weeks), the basal firing rate and the excitability of LHb neurons in brain slices was higher, whereas the amplitude of medium afterhyperpolarization and M-type K currents were smaller, when compared to ethanol naive rats. Concordantly, M-channel blocker (XE991)-induced increase in the spontaneous firing rate in LHb neurons was smaller. The protein expression of M-channel subunits, KCNQ2/3 in the LHb was also smaller. Moreover, anxiety levels (tested in open field, marble burying, and elevated plus maze) were higher, which were alleviated by LHb inhibition either chemogenetically or by local infusion of the M-channel opener, retigabine. Intra-LHb infusion of retigabine also reduced ethanol consumption and preference. These findings reveal an important role of LHb M-channels in the expression of AUDs and ADs, and suggest that the M-channels could be a potential therapeutic target for alcoholics.

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

“…Importantly, LHb hyperactivity facilitates anxiogenesis (Pobbe and Zangrossi, 2008). We recently reported that during withdrawal from repeated cycles of ethanol consumption, rats showed pronounced anxiety-like behaviors (Kang et al, 2017). Therefore, inhibition of LHb CaMKII-AMPAR signaling may also mitigate anxiety-like behaviors in ethanol-withdrawn rats.…”

“…Electrophysiological recordings were conducted as described (Kang et al, 2017; Zuo et al, 2013). Electrophysiological events were recorded with an Axon 200B amplifier, a Digidata 1440A A/D converter, and Clampfit 10.6 software (Molecular Devices Co., Union City, CA, USA).…”

“…Three weeks after virus injection, CNO (10 mg/kg, i.p.) was given 30 min before accessing to ethanol or forced swimming test (Kang et al, 2017). …”

Control of behavioral flexibility by the lateral habenula

“…Chronic exposure to stress leads to a degradation of the LHb, further supporting its role in signaling stress (Jacinto et al 2016). In addition to ethological stressors, the LHb has also been strongly linked with cocaine and ethanol withdrawal stress responses (Neumann et al 2014; Meye et al 2016; Kang et al 2017). Alterations in inhibitory tone in the LHb selectively during drug withdrawal drive negative symptoms and may contribute to continued drug seeking (Meye et al 2016; Kang et al 2017).…”

“…In addition to ethological stressors, the LHb has also been strongly linked with cocaine and ethanol withdrawal stress responses (Neumann et al 2014; Meye et al 2016; Kang et al 2017). Alterations in inhibitory tone in the LHb selectively during drug withdrawal drive negative symptoms and may contribute to continued drug seeking (Meye et al 2016; Kang et al 2017). How these pathological states alter normal behavioral flexibility processes within the LHb remains unclear.…”