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Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3preferring antagonist PNU‐99194A: an analysis of possible mechanisms

 

作者: A.J. Goudie,   L.E. Baker,   J.A. Smith,   A.J. Prus,   K.A. Svensson,   L.A. Cortes‐Burgos,   E.H.F. Wong,   S. Haadsma‐Svensson,  

 

期刊: Behavioural Pharmacology  (OVID Available online 2001)
卷期: Volume 12, issue 5  

页码: 303-315

 

ISSN:0955-8810

 

年代: 2001

 

出版商: OVID

 

关键词: drug discrimination;rat;dopamine;clozapine;schizophrenia;D3‐preferring antagonists;PNU‐99194A;scopolamine;trihexyphenidyl;receptor binding

 

数据来源: OVID

 

摘要:

Dopamine D3receptors 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 thein vivoactions of the atypical antipsychotic clozapine and the putative D3‐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 D3‐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 D3antagonism, the D3‐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 vitroreceptor binding studies with M1−M5receptors indicated that (with the possible exception of the M4receptor), 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 D3receptor, 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 D3receptors; (2) D3antagonism does not play a critical role in the clozapine stimulus (since D3‐preferring antagonists did not consistently induce generalization to clozapine); (3) although D3antagonism plays a role in the PNU‐91994A stimulus (since the D3‐preferring antagonist (+)‐UH 232 induced full generalization, in accord with results from prior studies with other D3‐preferring antagonists), the PNU‐99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. Thein vivodifferences observed between PNU‐99194A and other D3‐preferring antagonists should be borne in mind when this agent is used as a tool to study D3receptor functioningin 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.

 

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