The use of histochemistry in pharmacological studies.

THERE are two general approaches to the cytological localization of sites of drug action: (1) demonstration of the distribution of the active drug, or a close analog, at the cellular level following its systemic admini,stration, and (2) the demonstration at discrete loci of changes in the concentration of a specific group or compound with which the drug is known to react to produce its characteristic pharmacological effects. Several types of microscopic techniques which either have been employed or have potential ,usefulness for the first approach are listed in Table I (I). Some of these will b,e discussed in detail in the subsequent papers of this symposium. All require carefully controlled conditions to eliminate or minimize artifactual localization due to diffusion of the drug, during the preparation of sections, from its location in vivo at the time of sacrifice. However, the major reservation to the interpretation of results obtained with these methods is that in general they can indicate only potential sites of drug action. On the basis of several factlors, including aqueousand lipoid-solubility, ionic ‘or induced charge, and molecular size and shape, a drug may be distributed at several cellular sites, or even tissues or organs, in addition to those where it combines with specific receptors or enzyme systems to produce its major pharmacological effects. An obvious example is the concentration of ether and other central nervous system depressants in the subcutaneous fat. The second approach avoids the latter disadvantage, but is limited by the fact that the reactive groups or compounds with which most drugs combine are either unknown or not readily subject to demonstration or quantification. A few active groups and enzymes, for which there is reasonable assurance that they represent the major sites of