The Effect of Typical and Atypical Antipsychotics on the MK-801 Induced Deficit in Behavioural Inhibition

The non-competitive NMDA receptor antagonist (+)-5-methyl-10, 11-dihydro- 5H-dibenzo [a, d,] cyclohepten-5-10-imine maleate (MK-801) has been shown to produce deficits in behavioral inhibition measured as the lack of extinction during operant procedures. As such, MK-801 has the potential to be used as a preclinical animal model of cognitive deficits that arise in schizophrenia. The present thesis sought to explore if typical and/or atypical antipsychotics have the ability to reverse deficits in behavioral inhibition (lack of extinction) seen following MK-801 administration. In addition, immunohistochemical labeling of pERK1/2 in the infralimbic cortex (IL) was examined after extinction lever pressing to determine the importance of the IL in mediating these behavioral changes. A dose-response curve revealed an extinction deficit following administration of 0.1 mg/kg of MK-801. The 0.1 mg/kg dose of MK-801 was also associated with a decrease in IL pERK1/2 labeling. Administration of the typical antipsychotic, Flupenthixol, did alter MK-801 effects on extinction bar pressing at the 0.25 mg/kg and 0.5 mg/kg doses. The highest dose of Flupenthixol also increased pERK1/2 labeling compared to MK-801 administration on its own. Administration of the atypical antipsychotic Clozapine did not alter extinction pressing following MK-801 and did not alter pERK1/2 labeling. Aripiprazole, given at 1 mg/kg, decreased MK-801 induced bar pressing to that of the saline control group but there were no differences in pERK1/2 labeling in the IL. The data suggest that MK-801 does induce deficits in behavior inhibition that may be dependent on dopamine neurotransmission. The increased pERK1/2 labeling in the IL following administration of 0.5 mg/kg of Flupenthixol highlights the importance of the IL in extinction learning. However, the IL is unlikely to be solely responsible for extinction learning as the 0.25 mg/kg dose of Flupenthixol and the 1 mg/kg dose of Aripiprazole decreased non-rewarded operant responding following MK-801 but did not alter IL pERK1/2 labeling.

Name thesis:degree_name

Master of Science (M.Sc.)

Level thesis:degree_level

Master's

Discipline thesis:degree_discipline

Neuroscience

Grantor dc:publisher

Carleton University

Year dc:date.issued

2014

Author dc:creator

• Tuplin, Erin

Statement dc:rights

• Copyright © 2014 the author(s). Theses may be used for non-commercial research, educational, or related academic purposes only. Such uses include personal study, research, scholarship, and teaching. Theses may only be shared by linking to Carleton University Institutional Repository and no part may be used without proper attribution to the author. No part may be used for commercial purposes directly or indirectly via a for-profit platform; no adaptation or derivative works are permitted without consent from the copyright owner.

Language dc:language.iso

en

DOI

10.22215/etd/2014-10451

OAI identifier oai:identifier

oai:carleton.scholaris.ca:20.500.14718/38551