A molecular mechanism for choosing alcohol over an alternative reward

Abstract

Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.

Sensitivity to gains during risky decision-making differentiates chronic cocaine users from stimulant-naïve controls

“…Neurobehavioral research has sought to identify the neuroplastic adaptations underlying disadvantageous decision-making [23,24], suggesting that chronic cocaine users (CU) are less sensitive to gains (i.e., magnitude of positive outcomes) and losses (i.e., magnitude of negative outcomes) in everyday situations [25,26]. Particularly, CU have been proposed to suffer from a generalised impairment in value representation, reflected in blunted neural responses to nonsubstance-related (social and non-social) rewards, specifically in value-coding regions such as ventromedial prefrontal cortex [3,27,28]. Based on these findings we hypothesize that the deficits of chronic cocaine use in risky decision-making partially arise from alterations in return sensitivity.…”

An imperfect model is still useful

“…Another recent study uncovered a genetic mechanism governing preference for alcohol over a sweet solution. This phenotype, present only in 12% of rats tested , was associated with other behaviours characteristic of alcohol use disorder, such as continued use despite adverse outcomes. Most importantly, it was associated with a change in gene expression that was paralleled in post‐mortem tissue of humans with alcohol use disorder .…”

“…This implies that findings in animal models, where neural mechanisms can be described with greater detail, can be used to derive hypotheses regarding human neural activity. Researchers are also now studying similar behaviours and brain loci using animals with a more prolonged history of voluntary drug intake or in animals that show preference for drugs over ‘natural’ reinforcers . This may open the door to understanding differences between normal and pathological reward‐seeking, as well as brain mechanisms that underlie the transition between these states.…”

“…Therefore, animal studies can reproduce key endophenotypes that at least relate to human alcohol use disorders and explore why these occur in some subjects but not others. Increasingly, animal research is embracing individual variability rather than unitary response patterns, and complementary findings between animal studies and human experience have ensued . Judicious examination of both intraspecies individual differences as well as interspecies similarities may provide a powerful tool for understanding the (patho)physiology that drives maladaptive reward‐seeking; knowledge that may ultimately lead to more effective strategies for tackling SUD.…”

“…Considered application of findings from animal models can inform human research. Furthermore, findings from human participants can be back‐translated and tested in animal models to provide evidence of functional mechanisms driving substance use . We agree that animal models should never seek to replace well‐thought‐out research that examines human behaviour.…”