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.