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

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Tuplin, Erin




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
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
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.






Carleton University

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Master of Science: 

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Theses and Dissertations

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