Adam J. Prus

Date of Award


Degree Name

Master of Arts



First Advisor

Dr. Lisa Baker

Second Advisor

Dr. Jack Michael

Third Advisor

Dr. Alan Poling

Access Setting

Masters Thesis-Open Access


Clozapine (CLZ) is an atypical antipsychotic with negligible extrapyramidal side-effects. Unfortunately, CLZ drug discrimination (DD) research has yielded inconsistencies with CLZ's known pharmacological characteristics. Porter et al. (2000) have suggested that the standard 5.0 mg/kg CLZ training dose is too high, thus accounting for difficulty in assessing clozapine's discriminative stimulus (SD) effects. Therefore, 16 male Sprague-Dawley rats were trained to discriminate either 1.25 (Group II) or 5.0 mg/kg (Group I) CLZ from vehicle in a two-choice DD task. The typical anti psychotic haloperidol (0.1-0.4 mg/kg) did not substitute for either CLZ SD, with the exception of one Group I subject for a 0.4 mg/kg haloperidol dose. The muscarinic M1 antagonist trihexyphenidyl engendered full substitution in Group II but not Group I subjects. The atypical antipsychotic melperone (0.375-3.0 mg/kg) also engendered full substitution in both groups, but at a dose (3.0 mg/kg) that severely disrupted responding. The 5-HT1A agonist 8-OH-DPAT (0.04-0.16 mg/kg) and the 5-HT2A antagonist MDL 100907 (0.03125-1.0 mg/kg) displayed only partial generalization in both groups. Haloperidol (0.05 mg/kg) plus 8-OH-DPAT and haloperidol (0.05-0.1 mg/kg) plus MDL 100907 combinations produced greater CLZ-appropriate responding than each drug tested alone, but only Group II subjects exhibited greater than 80% CLZ-appropriate responding to a 0.1 mg/kg haloperidol and 0.12 mg/kg MDL 100907 dose. Given similar data between groups, claims that a 1.25 mg/kg CLZ SD is more indicative of clozapine's atypical profile are questionable.