Academic journal article Alcohol Research

The Molecular Basis of Tolerance

Academic journal article Alcohol Research

The Molecular Basis of Tolerance

Article excerpt

Tolerance to a drug, including alcohol, was first described as a form of behavioral plasticity and was defined as a decreased response to repeated drug exposures (Kalant 1998). Tolerance can be described at different levels of biological complexity--molecular, cellular, and behavioral--or by its temporal characteristics of how rapidly the alcohol affects the organism.

Behavioral tolerance is measured at the level of the activity of an entire animal, resulting from mutual interactions in several brain structures and with other systems. For example, a simple walk on a straight wooden beam is a good measure of a mouse's coordination and sense of balance. Several brain regions (e.g., visual cortex, occipital cortex, cerebellum) "talk" to each other, as well as with other systems (e.g., muscular-skeletal) to enable the mouse to successfully walk from one end of the beam to the other. Alcohol intoxication impairs this complex coordination and a "drunken" mouse falls off the beam. An alcohol-tolerant mouse can, at least partially, retain its coordination and walk on the beam almost as well as an alcohol-abstinent mouse, in spite of the ingestion of alcohol (Grieve and Littleton 1979). Previous studies by Hoffman and Tabakoff (1989) have stressed the difference between "intrinsic" tolerance, which results from changes within the neurons controlling a behavior, and "extrinsic" tolerance, which results in behavioral adaptation via alterations in compensatory neural circuits (i.e., not via molecular tolerance within the primary neural circuit).

Currently, behavioral tolerance is divided into three categories: acute, rapid, and chronic (Crabbe et al. 1979; Kalant 1998; LeBlanc et al. 1975) (figure 1). Acute tolerance develops within a single drinking session, typically within minutes, whereas chronic tolerance occurs after a longer time, usually following days of continuous or intermittent alcohol exposure. Rapid tolerance shares many similarities with chronic tolerance but develops faster, typically within 8 to 24 hours.

Cellular tolerance typically is assessed at the level of a neuronal tissue consisting of a network of many neuronal and supportive cells, or even a single neuron.

Knowledge of molecular tolerance comes from dissecting adaptational processes developed by individual molecules (e.g., ion channels) during exposure to a drug. The current notion is that even complex behavioral traits can be traced to individual molecules. All of alcohol's complex effects on an organism start at the molecular level, during interaction of an alcohol molecule with its molecular target(s).

Although these interactions at the molecular level are complex, the level of complexity increases at the cellular and behavioral level because of multiple, complex, intertwined pathways that contribute to the development of tolerance. It still is unclear how interactions with molecules in the brain eventually can lead to the altered behavior defined as alcohol dependence. However, there is a great deal of information on the mechanism of tolerance at the molecular level; thus, this review will focus primarily on that level and discuss potential relationships with other levels, such as acute, rapid, and chronic tolerance at the behavioral level, when possible.


At the molecular level, our discussion will first address mechanisms involving modification of a mature, functional ion channel present in the neuronal plasma membrane and then move progressively upstream to the nucleus, site of the "birth" of the channel protein (see sidebar). The approach in this article will be to focus on a single channel type, the BK channel--a potassium ion channel of high conductance regulated by both voltage and calcium--that has been implicated in the onset of tolerance. This review focuses on the BK channel for several reasons: (1) This channel is abundantly expressed in many brain regions (MacDonald et al. …

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