Discriminative stimulus properties of 1.25 and 5.0 mg/kg doses of clozapine in rats: Examination of the role of dopamine, serotonin, and muscarinic receptor mechanisms

Clozapine (CLZ), an atypical antipsychotic drug (APD), produces minimal extrapyramidal side effects (EPS) and has significant advantages for treating both positive and negative symptoms in schizophrenic patients. CLZ has been established as a discriminative cue in the drug discrimination paradigm and in generalization tests the CLZ cue is more selective for atypical, rather than typical, APDs. However, greater selectivity for atypical antipsychotics has been demonstrated with a lower (1.25 mg/kg) CLZ training dose in rats [Psychopharmacology, 149 (2000) 189], rather than the traditional, higher training dose (5.0 mg/kg). It is therefore of interest to evaluate the properties mediating the 1.25 mg/kg CLZ discriminative cue. In the present study, rats were trained to discriminate either 1.25 mg/kg (N=7) or 5.0 mg/kg (N=7) CLZ from vehicle in a two-lever drug discrimination task. The typical antipsychotic haloperidol (0.1-0.4 mg/kg) did not substitute for either CLZ cue, whereas the atypical antipsychotic melperone (0.37-3.0 mg/kg) provided full substitution in both groups (>80% CLZ-appropriate responding). The 5-HT _1A receptor agonist (+)-8-OH-DPAT (0.04-0.16 mg/kg), and the selective 5-HT_2A receptor antagonist M100907 (0.03-1.0 mg/kg) did not produce substitution in either group. (+)-8-OH-DPAT combined with haloperidol (0.05 mg/kg) engendered only partial substitution (>60% CLZ-appropriate responding) for both CLZ cues, and M100907 combined with haloperidol (0.05 and 0.1 mg/kg doses) failed to provide substitution in either group. Trihexyphenidyl (0.18-6.0 mg/kg), a muscarinic M₁-preferring receptor antagonist, engendered full substitution for the 1.25 mg/kg CLZ cue, but only partial substitution for the 5.0 mg/kg CLZ cue. These results provide evidence that antagonism at the muscarinic M₁ receptor is sufficient to provide 1.25 mg/kg CLZ-like discriminative stimulus effects.