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

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.