Abstract
The present study examined the role of muscarinic receptors in the discriminative stimulus properties of clozapine. One group of rats was trained to discriminate the atypical antipsychotic clozapine (CLZ, 5.0 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (SCP, 0.125 mg/kg, IP) from saline. Complete cross-generalization was obtained for SCP in the CLZ-trained rats and for CLZ in the SCP-trained rats. The M1 muscarinic antagonist trihexyphenidyl substituted completely for both CLZ and SCP; however, the M2 antagonist BIBN 99 failed to substitute for either CLZ or SCP. In other substitution tests, the tricyclic antidepressant amitriptyline, the antihistamine promethazine, and cyproheptadine (5-hydroxytryptamine [5-HT] 2A/5-HT 2C, histamine, and muscarinic antagonist) substituted completely for CLZ and SCP. The tetracyclic antidepressant mianserin substituted completely in the CLZ-trained rats, but did not substitute for SCP. Compounds that produced partial substitution included the tricyclic antidepressant imipramine, the anxiolytic chlordiazepoxide, and the antipsychotic thioridazine. Other compounds tested only in the CLZ-trained rats that failed to produce reliable CLZ-appropriate responding included N-methyl- d-aspartic acid (NMDA, selective agonist for glutamate receptors), metergoline (5-HT 2A/5-HT 2C antagonist), propranolol (beta noradrenergic antagonist), and phentolamine (alpha noradrenergic antagonist). All of the compounds that produced CLZ-appropriate responding (except for mianserin) display high binding affinities for muscarinic cholinergic receptors. The results of the present study demonstrated that muscarinic receptors (especially M1) play an important role in the mediation of the discriminative stimulus properties of CLZ in rats, and provide additional support for the importance of CLZ's anticholinergic properties as part of it's unique profile as an atypical antipsychotic.
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