Discriminative Stimulus Effects

One useful method of evaluating the pharmacological characteristics of PCP, as well as a variety of other drugs, is the drug-discrimination procedure. Typically, animals that are slightly food restricted are trained to respond for food on one lever after drug administration and on another lever after saline. On days when the drug is administered before the session, responding on the drug-associated lever results in food delivery while responding on the saline-associated lever does not. Conversely, on days when saline is administered before the session, responding on the saline-associated lever results in food delivery while responding on the drug-associated lever does not. After a number of training days, animals learn to reliably respond on the drug lever after the drug injection and on the saline lever after saline injection. Once this discrimination has been established, a number of test drugs can be administered to determine whether or not they produce effects similar to the training drug. Test drugs that substitute for the training drug (i.e., cause responses on the drug-associated lever) are assumed to have discriminative stimulus effects that are similar to the training drug.

Using this procedure, several investigators have shown that PCP and other noncompetitive antagonists produce similar discriminative stimulus effects in a number of different species (see Willetts, Balster, & Leander, 1990 for a review). These results suggest that the mechanisms of action of PCP and other noncompetitive antagonists, such as ke-tamine and dizocilpine, are similar. Furthermore, the discriminative stimulus effects of competitive antagonists such as CGS 19755, NPC 12626 and CPP were also similar to each other, which is again consistent with the notion that the mechanisms of action of competitive antagonists are similar. Given that competitive and noncompetitive antagonists both reduce neuronal firing, it was of interest to compare the discriminative stimulus effects of these two types of antagonists. In most species, the discriminative stimulus effects of competitive and noncompetitive antagonists are very different from each other.

Another difference between the competitive and noncompetitive antagonists lies in their abilities to antagonize the discriminative stimulus effects of NMDA. While both types of antagonist are effective in blocking the convulsant and lethal effects of NMDA, competitive antagonists in general are much more effective than noncompetitive antagonists in blocking the discriminative stimulus effects of NMDA. The noncompetitive antagonists partially antagonize NMDA but only at doses that produced substantial behavioral suppression. While most effects of NMDA are antagonized by both competitive and noncompetitive antagonists, the behavioral-suppressing effects of noncompetitive antagonists often interfere with their ability to antagonize the discriminative stimulus effects of

NMDA.

Finally, another important finding with competitive and noncompetitive antagonists involve their interaction with other receptor systems. Studies show that the discriminative stimulus effects of competitive antagonists such as CPP and NPA 12626 are similar to those produced by the BARBITURATE pentobarbital. Under certain conditions, the discriminative stimulus effects of PCP and pentobarbital were also similar. In addition to the interactions of NMDA antagonists with barbiturate receptors, some investigators have found similarities between PCP and ethanol (alcohol). These studies have proven to be important in describing both the similarities and differences between the noncompetitive and competitive NMDA-receptor antagonists.

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