CommentarySome implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists
Section snippets
Constraints on response detection as a determinant of drug effects
First, this model supposes that the tissue is able to generate graded effects across all drug doses from the lowest active dose sufficient to bind a single receptor to a maximal dose that binds all receptors. Moreover, this model supposes the existence of an experimental procedure that can detect and differentiate effects across this entire range. In practice, neither premise holds [7]. Some threshold level of tissue response is required before a signal can be detected by the experimental
Preexisting receptor activity (tone) as a determinant of drug effects
A second simplification of the original model of occupation theory lies in its assumption that target receptors in a tissue are quiescent prior to delivery of the drug. Again, though, this premise does not appear to hold under many circumstances. Rather, drug effects on receptor activity are often integrated with some preexisting level of receptor activity, which can be referred to as the “tone” of the receptor system. There are at least two sources of tone, and of interest for the present
Implications
The ability of drugs to produce agonist, antagonist or inverse agonist effects in vivo depends not only on features inherent to the drug, but also on characteristics of the assay system and on the magnitude and source of preexisting levels of receptor activity, or tone. The dependence of drug phenotypes on tissue and assay conditions indicates that, at the very least, care should be taken to cultivate an awareness of the constraints that any particular assay imposes on the detection of
Acknowledgement
This work was supported in part by R01-DA11460 from the National Institute on Drug Abuse, NIH.
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