NMDA Antagonists and Tolerance to Drugs Affecting the Central Nervous System

Tolerance is usually defined as a reduction in the effects for the drug in question such that a higher dose (or blood concentration) of the drug is required to produce the same degree of effects as seen previously in the drug-naive individual. Tolerance is a complex phenomenon that develops as a result of adaptation of the organism to the presence of drugs in certain circumstances and can develop to different drug effects at different rates (28,33,39,40,100). Investigators are interested in studying tolerance for multiple reasons, ranging from its role in addiction to neuroadaptation or neuronal plasticity (for details, see 38,39, 64). Tolerance can develop and be measured within three different time frames. The most commonly studied form of tolerance, called chronic tolerance, increases gradually over days or weeks of drug administration. It usually includes both functional and dispositional components. Acute tolerance differs from chronic tolerance in that the former develops within a single exposure to the drug. The fact that such tolerance is seen even when the drug effect is related directly to the concentration in the brain (66) makes it clear that acute tolerance is indeed functional in nature. Another form, called rapid tolerance, is seen as a reduction in response to a second dose of drug that is given 8–24 h after the effect of the first dose has disappeared. Rapid tolerance is functional rather than dispositional. Although the existence of rapid tolerance has been known for nearly 20 years, its relationship to chronic tolerance has not been studied systematically until recently (38,51). Recent experiments indicate that rapid tolerance and chronic tolerance are closely related and suggest possible similarities between the mechanisms of rapid and chronic tolerance (44). Both rapid tolerance and chronic tolerance have been shown to be influenced by, or to require, processes related to learning and memory. However, no similar comparison of acute tolerance with the other two forms has yet been carried out. Therefore, the nature of the relationship among these three time courses of tolerance and the question of whether they rest upon the same or different mechanisms is not clear.