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 schizophren ia and the actions of antipsychotic drugs. The initial studies reported her e 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 clo zapine consistently generalized to PNU-99194A in two separate studies. Howe ver, 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 D3 antagonism, the D3-preferring antag onist (+)-UH 232 and clozapine both induced full generalization. However, t he PNU-99194A-trained animals also generalized fully to the muscarinic anta gonists scopolamine and trihexyphenidyl. A possible explanation for the sym metrical generalization observed between clozapine and PNU-99194A is that t hese drugs have common muscarinic antagonist actions, since muscarinic anta gonists have been reported to substitute for clozapine in numerous prior st udies. However, in vitro receptor binding studies with M-1-M-5 receptors in dicated that (with the possible exception of the M-4 receptor), no muscarin ic receptor subtype had high affinity for both clozapine, PNU-99194A and sc opolamine. In addition, other binding studies indicated that whereas clozap ine and PNU-99194A had high affinity for the D3 receptor, scopolamine did n ot. It is therefore concluded that: (1) The generalization seen between clo zapine, PNU-99194A and muscarinic antagonists may be mediated by common eff ects 'downstream' from either muscarinic or D-3 receptors; (2) D-3 antagoni sm does not play a critical role in the clozapine stimulus (since D-3-prefe rring 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 a ccord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscar inic antagonists and clozapine. The in vivo differences observed between PN U-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 tentativ ely that compounds with a profile like PNU-99194A may have antipsychotic ac tions similar to clozapine. Some preclinical data are suggestive of such ef fects of PNU-99194A. (C) 2001 Lippincott Williams & Wilkins.