Tolerance to alcohol: A critical yet understudied factor in alcohol addiction

Abstract

Alcohol tolerance refers to a lower effect of alcohol with repeated exposure. Although alcohol tolerance has been historically included in diagnostic manuals as one of the key criteria for a diagnosis of alcohol use disorder (AUD), understanding its neurobiological mechanisms has been neglected in preclinical studies. In this mini-review, we provide a theoretical framework for alcohol tolerance. We then briefly describe chronic tolerance, followed by a longer discussion of behavioral and neurobiological aspects that underlie rapid tolerance in rodent models. Glutamate/nitric oxide, γ-aminobutyric acid, opioids, serotonin, dopamine, adenosine, cannabinoids, norepinephrine, vasopressin, neuropeptide Y, neurosteroids, and protein kinase C all modulate rapid tolerance. Most studies have evaluated the ability of pharmacological manipulations to block the development of rapid tolerance, but only a few studies have assessed their ability to reverse already established tolerance. Notably, only a few studies analyzed sex differences. Neglected areas of study include the incorporation of a key element of tolerance that involves opponent process-like neuroadaptations. Compared with alcohol drinking models, models of rapid tolerance are relatively shorter in duration and are temporally defined, which make them suitable for combining with a wide range of classic and modern research tools, such as pharmacology, optogenetics, calcium imaging, in vivo electrophysiology, and DREADDs, for in-depth studies of tolerance. We conclude that studies of the neurobiology of alcohol tolerance should be revisited with modern conceptualizations of addiction and modern neurobiological tools. This may contribute to our understanding of AUD and uncover potential targets that can attenuate hazardous alcohol drinking.

Keywords: Alcohol dependence; Alcohol use disorder; Alcoholism; Drug addiction; Ethanol; Preclinical models; Rodent models.

Figure 1.. PubMed results of articles published between 1960 and 2020 referencing alcohol tolerance or alcohol drinking in rodents.

PubMed was searched on December 31^st, 2020. The following search terms for alcohol tolerance (blue bars) and alcohol drinking (black bars) were used: (alcohol[ti] OR ethanol[ti]) AND (tolerance[tw] OR tolerant[tw]) AND (rat[tw] OR rats[tw] OR mice[tw] OR mouse[tw]). Search terms for alcohol drinking (black bars): (alcohol[ti] OR ethanol[ti]) AND (drinking[tw] OR “self-administer”[tw] OR “self-administered”[tw] OR “self-administers”[tw] OR “self-administration”[tw] OR consume[tw] OR consumed[tw] OR consumes[tw] OR consumption[tw]) AND (rat[tw] OR rats[tw] OR mice[tw] OR mouse[tw]). The search yielded a total of 1,882 articles for tolerance and 12,847 articles for drinking.

Figure 2.. Alcohol consumption and motor coordination in mice.

(a) Alcohol intake (g/kg in 2 h) in mice in the drinking-in-the-dark paradigm, in which mice could drink from a single bottle that contained 20% alcohol (v/v) 3 h into their dark phase. A separate cohort of mice received water instead of alcohol and served as controls (water intake not shown). (b) Motor coordination in the balance beam test, which consisted of a long and narrow wood block that was elevated above the floor. After training the mice to traverse the wood block, they were tested immediately after the 8^th and 15^th drinking-in-the-dark sessions. Mice that were exposed to drinking-in-the-dark exhibited motor incoordination during the 8^th session but not during the 1^5th session compared with the mice that drank water only. Modified from Linsenbardt et al. (2011), with permission.

Figure 3.. Dose-response curve for alcohol-induced hypothermia and the development of rapid tolerance.

Alcohol dose-dependently produced hypothermia in mice, an effect that decreased, regardless of dose, when the mice were tested with the same doses on day 2. Taken with permission from (Crabbe et al., 1979).