A role for circuitry of the cortical amygdala in excessive alcohol drinking, withdrawal, and alcohol use disorder

Abstract

Alcohol use disorder (AUD) poses a significant public health challenge. Individuals with AUD engage in chronic and excessive alcohol consumption, leading to cycles of intoxication, withdrawal, and craving behaviors. This review explores the involvement of the cortical amygdala (CoA), a cortical brain region that has primarily been examined in relation to olfactory behavior, in the expression of alcohol dependence and excessive alcohol drinking. While extensive research has identified the involvement of numerous brain regions in AUD, the CoA has emerged as a relatively understudied yet promising candidate for future study. The CoA plays a vital role in rewarding and aversive signaling and olfactory-related behaviors and has recently been shown to be involved in alcohol-dependent drinking in mice. The CoA projects directly to brain regions that are critically important for AUD, such as the central amygdala, bed nucleus of the stria terminalis, and basolateral amygdala. These projections may convey key modulatory signaling that drives excessive alcohol drinking in alcohol-dependent subjects. This review summarizes existing knowledge on the structure and connectivity of the CoA and its potential involvement in AUD. Understanding the contribution of this region to excessive drinking behavior could offer novel insights into the etiology of AUD and potential therapeutic targets.

Keywords: alcohol dependence; alcohol use disorder; circuit; cortical amygdala; substance use disorder; withdrawal.

Figure 1:. Projections of the CoA to brain regions relevant to Alcohol Use Disorder:

Anatomical annotations (Eleftheriades, Creatsas, & Nicolaides) from the Allen Mouse Brain Atlas and 2-photon tracing of retrograde AAV injected to the CoA (right). Allen Mouse Brain Atlas, mouse.brain-map.org and atlas.brain-map.org. Allen Mouse Brain Connectivity Atlas, https://connectivity.brain-map.org/A. Central Amygdala (black) and Basolateral Amygdala (brown) and Cre-dependent AAV tracing of axonal projections from an injection site in CoA (purple). B. cre-dependent AAV tracing of axonal projections from an injection site in CoA. Left: BNST (yellow); data from Slc17a7-IRES-cre mice, Experiment 267150949 Allen Brain Atlas.

Figure 2:. Projection in CoA with the 3D Brain Explorer:

A. 3D brain retro network of Slc17a7-IRES2-Cre mice (representing glutamatergic projections from the CoA) with retrograde tracer injection in CoA (EGFP). B. 3D brain retro network of Gad2-IRES-Cre mice (representing GABAergic neurons within the CoA) with retrograde tracer injection in CoA (EGFP). Data from Slc17a7-IRES-cre mice, experiment 267150949 and Gad2-IRES-cre mice experiment 302740314 Allen Brain Atlas.

Figure 3:. Connectivity of the CoA to other brain regions.

This figure highlights several brain regions that send projections to the CoA (black arrows) and those that the CoA projects to (green arrows). The projections highlighted are those primarily relevant to alcohol drinking behavior. The CoA (orange) receive inputs from the AOB (cyan) and MOB (green). The CoA projects to the BNST (blue), CeA (red), BLA (purple) and vHPC (aqua). BNST, bed nucleus of the stria terminalis; BLA, basolateral amygdala; CeA, central nucleus of the amygdala; AOB, accessory olfactory bulb; MOB, main olfactory bulb.

Figure 4:. Hypothesized involvement of signaling of CoA to BLA, CeA, and BNST circuits during alcohol dependent drinking.

We hypothesize that during alcohol withdrawal, there is increased activity of neurons in the CoA resulting, in increased glutamatergic output to the CeA, BNST, and BLA that contributes to excessive alcohol drinking.