Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D 3 preferring antagonist PNU‐99194A: an analysis of possible mechanisms

Dopamine D 3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D 3 ‐preferring antagonist PNU‐99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU‐99194A in two separate studies. However, four other putative D 3 ‐preferring antagonists (PD 152255, (+)‐S14297, nafadotride and (+)‐AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU‐99194A, which has been suggested to induce a stimulus mediated specifically by D 3 antagonism, the D 3 ‐preferring antagonist (+)‐UH 232 and clozapine both induced full generalization. However, the PNU‐99194A‐trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU‐99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M 1 −M 5 receptors indicated that (with the possible exception of the M 4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU‐99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU‐99194A had high affinity for the D 3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU‐99194A and muscarinic antagonists may be mediated by common effects ‘downstream’ from either muscarinic or D 3 receptors; (2) D 3 antagonism does not play a critical role in the clozapine stimulus (since D 3 ‐preferring antagonists did not consistently induce generalization to clozapine); (3) although D 3 antagonism plays a role in the PNU‐91994A stimulus (since the D 3 ‐preferring antagonist (+)‐UH 232 induced full generalization, in accord with results from prior studies with other D 3 ‐preferring antagonists), the PNU‐99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU‐99194A and other D 3 ‐preferring antagonists should be borne in mind when this agent is used as a tool to study D 3 receptor functioning in vivo. The similarities between the PNU‐99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU‐99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU‐99194A.