The glutamate system dysfunctions present in schizophrenia raise new questions about possible glutamatergic actions of the atypical antipsychotic clozapine. While clozapine has been shown to partially substitute for the discriminative stimulus of the glutamate agonist N-methyl D-aspartate (NMDA) in rats, NMDA discrimination has not previously been established in mice. The present study was designed to explore the possible role of NMDA activity in clozapine’s discriminative stimulus. Two groups of C57BL/6 mice were trained to discriminate either 2.5 mg/kg CLZ from vehicle or 30 mg/kg NMDA from vehicle in a standard two-lever drug discrimination task. NMDA drug discrimination was successfully established in C57BL/6 mice. While NMDA did not substitute for clozapine, clozapine partially substituted for NMDA at the 0.625 mg/kg dose, demonstrating an asymmetrical relationship between clozapine’s and NMDA’s discriminative stimuli. Dose combination tests further investigated this relationship. It was found that 0.625 mg/kg CLZ + 30 mg/kg NMDA produced partial substitution (61.82% DLR), while 0.625 mg/kg CLZ + 56 mg/kg NDMA full substitution (92.82% DLR) in CLZ-trained mice. In addition, combination testing with 10 mg/kg NMDA + 2.5 mg/kg CLZ and 10 mg/kg NMDA + 5.0 mg/kg CLZ produced full substitution in NMDA-trained mice ((80.04% DLR and 100% DLR, respectively). Finally, it was found that the α1- adrenoreceptor antagonist prazosin fully substituted for both CLZ (3.0 mg/kg = 92.20% DLR) and NMDA (1.0 mg/kg = 98.77% DLR and 3.0 mg/kg = 99.62% DLR). These findings suggest that interactions between clozapine’s and NMDA’s discriminative stimuli may involve antagonism of α1- adrenoreceptors, but further research of other mechanisms including serotonergic, histaminergic, and cholinergic receptor activity or metabolic interactions is needed. Finally, these initial finding suggest that that drugs active at glutamatergic receptors may have potential as therapeutic drugs for treatment of schizophrenia.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-2690 |
| Date | 24 April 2009 |
| Creators | Vunck, Sarah A. |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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