Combination of Sub‐effective Doses of NMDA and D1 Dopamine Receptor Antagonists Impairs Executive Function in Rats

Abstract

Contemporary research in the pathophysiology of cognitive deficits in schizophrenia has provided a multifactorial view, in which the neurotransmitters dopamine, gamma aminobutyric acid (GABA) and glutamate are disturbed in the prefrontal cortex (PFC) of schizophrenic brains. This view is supported by the fact that current antipsychotic drugs, which are primarily dopamine receptor blockers, are not effective in treating the cognitive symptoms of schizophrenia. We hypothesized that abnormality in dopamine, GABA and glutamate neurotransmissions act synergistically to cause certain cognitive symptoms of schizophrenia. We tested the effect of blockade of all three neurotransmitter systems on executive function using an operant conditioning‐based attentional set‐shifting task to assess behavioral flexibility. In a series of dose‐response studies, we determined the effective doses of the specific antagonists for dopamine D1 receptors (SH‐23390), GABA‐A receptors (bicuculline methiodide) and NMDA receptors (MK‐801). Next, sub‐effective doses were administered subcutaneously 25 min before the set‐shifting task. Our results indicate that while the single antagonist treatments did not impair set‐shifting, combination of sub‐effective doses of SH‐23390 and MK‐801 severely affected performance. Present findings will help to elucidate mechanisms underlying cognitive deficits in schizophrenia.Acknowledgement: Supported by NSERC and the Dept. of Psychiatry, University of Western Ontario.