The neurobiology of tolerance: Predicting alcohol use disorder

By Naveed Saleh, MD, MS | Medically reviewed by Alison Christy, MD, PhD
Published January 23, 2024

Key Takeaways

  • Alcohol tolerance is a poorly studied concept that requires further research in the treatment landscape for alcohol use disorder. 

  • It is unclear whether tolerance predicts alcohol use disorder, but research shows that greater resistance to the effects of alcohol impacts the progression to and severity of addiction.

  • Debate around whether or not tolerance can help predict alcohol use disorder exists, with more recent studies suggesting that in teenagers, specifically, the frequency of binge drinking episodes is more meaningful than an individual’s tolerance to alcohol’s effects.

Despite the ubiquitous presence of alcohol in today’s society, the effects of alcohol on the brain is poorly understood. One phenomenon that occurs with frequent consumption of alcohol is tolerance—meaning that with repeated use of alcohol, the same quantity feels less potent. 

Research gaps

Alcohol tolerance is an understudied phenomenon, despite its perceived role in dependence.

Gaps in research include sex differences, hedonic responses, the genetic and epigenetic basis of tolerance, and between-system neuroadaptations. Neurotransmitter and region-, pathway-, and cell type-specific effects also require further elucidation.

Current assessments of tolerance have been relatively simplistic, as discussed in a review published in Pharmacology Biochemistry and Behavior.[]

Historically, researchers have been more interested in the physiological processes associated with addiction and less interested in the mechanisms involved in the development of addiction. Research has focused on withdrawal, relapse, craving, and escalation of drug use, in which tolerance plays a role. 

Types of tolerance

Tolerance is an initial form of behavioral plasticity that is triggered by the ingestion of alcohol. It occurs in three forms: acute, rapid, and chronic. 

Experts writing in the Journal of Neuroscience explain that molecular mechanisms are specific to each form of tolerance, meaning dose, time, and pattern of exposure involve different plasticity mechanisms.[] It remains to be seen whether ethanol colocalizes in brain circuits, or if there are shared common plasticity mechanisms. Also unclear is the relative contribution of different brain circuits in the progression toward alcohol use disorder.

Learning from flies

Few other animals appreciate alcohol like humans do, but fruit flies—Drosophilia—respond to alcohol much like humans in regards to changes in social behavior, wobbly movements, learned preferences, withdrawal from alcohol, and development of ethanol tolerance. Acute, rapid, and chronic forms of tolerance are all evident and genetically specific in this fruit fly species.

Tolerance in Drosophilia is functional due to adaptive changes in behavior and not because of liver metabolism. In other words, tolerance is pharmacodynamic and not pharmacokinetic.

Using Drosophila, the researchers publishing in the Journal of Neuroscience identified molecular and neural circuit mechanisms for rapid and chronic ethanol tolerance.

Specifically, they found that rapid tolerance needs the induction of the immediate early gene (IEG) Hr38—an ortholog of mammalian Nr4a1-3—and histone deacetylase (HDAC) Sirt1 in the α/β lobes of the adult mushroom bodies, the principal learning and memory centers of the Drosophila brain. 

On the other hand, chronic tolerance is triggered by prolonged exposure to a low concentration of ethanol and occurs independently of Hr38. Chronic tolerance is stymied by Sirt1 in the γ lobes of the adult mushroom bodies. Moreover, unlike rapid tolerance, chronic tolerance mediates the induction of the c-fos-like IEG kayak via subsequent ethanol exposures. 

“Chronic exposure,” the authors wrote, “specifically forms a long-term memory (LTM)-like state that is distinct from both appetitive and aversive forms of LTM, whereas rapid tolerance exhibits characteristics of intermediate-term memory that is composed of labile and consolidated components.” 

They add, “Thus, ethanol tolerance uses some of the same brain circuitry as ethanol reward, but tolerance likely uses the circuitry differently.” 

Diagnostic relevance

The DSM defines tolerance as “a need for markedly increased amounts of alcohol to achieve intoxication or desired effect” and “markedly diminished effect with continued use of the same amount of alcohol.”

Two important takeaways from this DSM definition are that (1) it is a subjective, change-based definition, whereby users define their own perceptual changes regarding “effect” and “intoxication,” and (2) changes are more apparent during an individual’s early drinking experiences, before patterns are solidified.

There is debate regarding the relevance of tolerance in predicting alcohol use disorder. Early studies suggested that high tolerance increased risk of developing a use disorder, but later work found conflicting results. In particular, studies suggest that in teenagers, specifically, how frequently large quantities of alcohol are consumed matters more than the individual’s tolerance to alcohol’s effects.[]

What this means for you

Tolerance to alcohol, and how it impacts development and severity of addiction, is a poorly understood phenomenon in medicine. The DSM and other diagnostic criteria define tolerance by self-reported changing patterns in consumption, but it is a subjective element, and therefore subject to recall bias. Tolerance can be assessed by physicians for further consideration of alcohol use disorder, but it is likely not the only important factor in predicting the disorder. 

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