Nucleus accumbens shell cholinergic interneurons potently drive binge alcohol drinking: A commentary on Sharma et al., 2024

Glutamate- and GABA-expressing neurons have long been studied in relation to alcohol drinking (Wang et al., 2022), but less is known about the importance of interneurons. Some interneurons can help synchronize and integrate activity across principal neurons in a region. GABAergic interneurons, especially fast-spiking neurons, have been implicated in such larger-scale regulation and can influence alcohol drinking (Patton et al., 2021). Another important population is the cholinergic interneurons (CINs). These are generally in low abundance (<2% of cells) and have been widely studied for their role in providing tonic acetylcholine, phasic firing increases in response to rewards, interactions with dopamine during cues, and other roles (Mallet et al., 2019). CINs have been broadly investigated in the dorsal striatum (Mallet et al., 2019), but CIN importance in nucleus accumbens (NAc) areas has received less attention.

A recent publication in Alcohol: Clinical and Experimental Research from Sharma et al. (2024) examines the importance of CINs in the nucleus accumbens shell (NAcSh) for alcohol binge drinking in mice. The NAcSh has been linked to many aspects of motivated responding. Original studies suggested the importance of the NAcSh in novel and primary experiences, rather than conditioned and motor responses (Floresco, 2015). For example, NAcSh is needed for alcohol-paired contexts, not for alcohol cues, to promote alcohol intake (Chaudhri et al., 2010). In addition, many studies find that NAcSh inhibition in mice (using a variety of methods) reduces voluntary home-cage alcohol consumption, with no consistent impact on sweet fluid intake (Lei et al., 2019). However, modulating activity in NAcSh can influence hedonic feeding for palatable foods (Castro & Bruchas, 2019). Thus, NAcSh likely plays an important role in many translationally relevant behaviors, including alcohol drinking and responding for other high-value rewards.

The present paper provides useful new findings in our understanding of how NAcSh cholinergic signaling, caused by activity of local CINs, is able to alter alcohol drinking. This study examined alcohol consumption in male mice using the Drinking in the Dark (DID) model, with 3 days of 2-h/day access, and 4-h access on the fourth day (the day of binge testing). Mice were of the ChAT-Cre line, which is on a C57 background, and showed binge-level intake (>80 mg% blood alcohol) in the 4-h drinking session.

The authors use two complementary methods to inhibit NAcSh CIN function. One involved the use of excitatory and inhibitory chemogenetics, the broadly used tool to alter neuronal activity. The other utilized virus-based expression of a toxin that leads to cell-specific lesioning, a valuable but less often used method to determine the functional importance of particular cells. Toxin-based ablation is a useful complement to chemogenetics since DREADDs sometimes have limited expression or effectiveness in some brain connections. Both methods for inhibition of NAcSh CINs significantly decreased alcohol drinking to below binge levels, along with a significant reduction in blood alcohol levels. Thus, CIN activity in the NAcSh, and presumably activation of local acetylcholine receptors, plays an important role in driving high alcohol consumption, at least in male mice. In parallel, chemogenetic activation of NAcSh CINs increased alcohol drinking. Importantly, these different manipulations of NAcSh CINs had no impact on sucrose drinking under a similar DID schedule. Thus, these studies together demonstrate that NAcSh cholinergic signaling promotes binge-level alcohol consumption.

These studies set the stage for future work to more precisely define how NAcSh cholinergic signaling promotes alcohol intake. For example, it would be valuable to activate NAcSh CINs and look at activity patterns in other neurons in NAcSh and across the rest of the brain. This sort of functional mapping, where one inhibits or activates a particular cell type, and examines activity changes across the brain, is increasingly used to uncover functional impacts of a particular cell group (e.g., Haaranen et al., 2020). Other studies could focus on CIN modulation of synaptic throughput in the NAcSh, as demonstrated in the adjacent NAc core (Kolpakova et al., 2022). In addition, determining the exact pharmacology of cholinergic receptors that mediate NacSh CIN effects will be of value. Indeed, cholinergic receptor blockers such as varenicline can reduce alcohol drinking, at least in some people (Donato et al., 2021). CIN activity also increases dopamine in NAcSh, which could promote reward-directed behavior (Cachope et al., 2012), and it would be of interest to determine the importance of dopamine and other receptors in the ability of NAcSh CINs to promote of drinking.

It will also be valuable to understand how modulating NAcSh CINs impacts other alcohol-drinking models, including intermittent and continuous access and compulsion-like consumption, as well as operant responding to alcohol, especially seeking (responding without reward delivery). Comparing across behavioral models could help disentangle what is, and is not, promoted by NAcSh CIN activity.

It is also important to understand whether NAcSh CINs regulate alcohol drinking similarly or differently in females and males. Our lab found that orexin-1 receptors in the NAcSh promote binge drinking in male but not female mice (Kwok et al., 2021). Further, NAcSh oscillations, in synchrony with medial prefrontal cortex, better predict alcohol drinking in females during diestrus stage (when they drink more alcohol), relatives to females in estrus and males (Henricks et al., 2019). There are also sex differences in NAcSh regulation of responding to punished rewards, but not other aspects of risk (Truckenbrod et al., 2023). However, as the authors of this new paper discuss, relatively little is known overall about how sex hormones impact the activity of CINs. In addition, there are no sex differences in changes in NAcSh cholinergic markers in response to adolescent alcohol exposure (Hauser et al., 2021), or in ventral tegmental area GABA projections onto NAcSh CINs (Al-Hasani et al., 2021). There are also no sex differences in how adolescent alcohol increases pain and NAcSh signaling (Kelley et al., 2023), or in stress response activation of NAcSh neurons (Clark et al., 2023). Thus, one possibility is that multiple drivers of motivated behavior converge in NAcSh, but that mechanisms that promote higher female alcohol drinking, and often greater punishment-resistant drinking (Radke et al., 2021), are downstream of NAcSh.

Finally, CINs have a more identifiable tonic firing pattern (Mallet et al., 2019). In this regard, recent work has used NAc deep brain stimulation to improve self-control in binge-eating humans, where stimulation was triggered by endogenous activity that was prominent during cravings (Shivacharan et al., 2022). Thus, it might be possible to identify CIN firing activity in vivo in NAc during the drive to drink, and NAc stimulation during such periods could provide a novel therapy to counteract alcohol addiction.

In summary, this study gives us new information about the importance of NAcSh CINs for alcohol drinking. By specifically targeting NAcSh CINs with chemogenetic inhibition and excitation and toxin-based ablation, Sharma et al. (2024) demonstrate that NAcSh CINs can strongly promote binge alcohol drinking. These studies provide new mechanistic insights into CIN and NAcSh regulation of alcohol intake and may present new avenues for targeting binge alcohol drinking.

The author declares that there are no conflicts of interest.