Individual differences in aversive-stimulus processing — appears to explain alcohol use disorded (AUD) in mice

Why are some people able to control their alcohol drinking, whereas others feel compelled to drink — despite undesirable health, personal, and/or social consequences? Today’s topic is well suited for GEITP, because gene-environment interactions play a central role in alcohol use disorder (AUD). AUD is defined as “losing control over alcohol drinking to the point of compulsion” (i.e. consuming excessive amounts of alcohol, despite negative consequences of developing numerous diseases). Almost 20% of adults worldwide engage in heavy alcohol drinking episodes during their lifetimes; in the U.S. only about half of these heavy drinkers are able to control this habit, or quit drinking entirely — even when faced with adverse health consequences caused by heavy drinking. Neither individual differences that drive compulsion, nor (central nervous system; CNS) circuitry of compulsive alcohol intake, are well understood.

Authors [see attached article & editorial] demonstrate individual differences in neuronal activity that represent a newly described brain circuit in mice during early alcohol addiction. [Gee whizzikers, just think of that!! … genetics might be involved.] This neuronal activity predicts escalation of alcohol drinking from mild, to compulsive, amounts of consumption. People drink alcohol to excess for a variety of reasons; but, as the mouse model demonstrates [in the attached article], not all heavy drinkers become compulsive drinkers. Compulsive drinkers are able to bypass this aversion (physiological or emotional response to a stimulus indicating that an object, organism, or situation, should be avoided; it is normally accompanied by a desire to withdraw from, or avoid, the unpleasant stimulus).

It seems likely that a genetic predisposition underlies the likelihood of developing addictive alcohol intake; in this study, authors take a major leap forward to show individual differences in compulsion — specifically, the consumption of bitter and unpleasant quinine-adulterated alcohol — at the level of neuronal activity (this would be equivalent to drinking gin-and-tonics daily ☹ ] By measuring neuronal changes in intracellular calcium concentrations (as a proxy for neuronal electrical activity during alcohol drinking), the authors identified clusters of neuronal activity when mice licked tubes of alcohol.

The alcohol drinking–associated neuronal activity was found to be located in a circuit between the medial prefrontal cortex (mPFC) and dorsal peri-aqueductal grey (dPAG) of the brain stem. Multiple lines of evidence from animal models had previously suggested a role of the PFC in compulsive alcohol drinking; the PFC lies in the frontal cortex (just behind the forehead in humans) and is responsible for “executive” functions, i.e. judgment, decision-making, and behavioral mood control. These functions are impaired during drug and alcohol addiction, especially in severe AUD. Hence, authors focused in detail on anatomical studies of calcium tracers, which showed that this mPFC-dPAG circuit responds to unpleasant stimuli in the brain. The PAG, best known for its role in pain, has reciprocal connections with many addiction-relevant brain regions, including the PFC. Recent discoveries have extended the role of the PAG to punishment and aversion signals — both of which are aspects of compulsion and addiction. Thus, it is not surprising that this mPFC-dPAG circuit has a role in alcohol compulsive behavior.These data provide detail on brain-and-behavioral relationships that underlie the individual differences in compulsive alcohol drinking in mice.


Science 22 Nov 2019; 366: 1008-1012

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