# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 4 An Antiglutamatergic Activity of Antipsychotics May Be Co-Responsible for Hypofrontality  
As described, the change of composition of NMDARs can be considered the next mechanism of action of antipsychotic drugs. Chronic administration of antipsychotics changes the composition of NMDARs in a different way, depending on the brain area and the type of drug. NMDARs are richly represented on GABA-ergic interneurons and play an important role in the regulation of their activity. GABA-ergic interneurons regulate the corticolimbothalamic circuit that plays an important role in cognition. Disturbances in the circuit are suggested to explain hypofrontality in mental disorders, especially in schizophrenia. From a neurophysiological view, the corticolimbothalamic circuit is based on many anatomical structures, presented in Figure 7. Pathology taking place in those structures influences the neuronal activity in the circuit and results in hypofrontality and mental symptoms like cognitive dysfunctions and negative symptoms in schizophrenia. For that reason, antipsychotic-induced changes of expression of NMDAR subunits in the thalamus and hippocampus changing the activity of NMDARs can relate to the formation of cognitive dysfunctions and negative symptoms in schizophrenia in humans, as shown in Figure 7. The described mechanism may consist of a part of the not fully understood mechanism of hypofrontality.  
As showed, studied antipsychotics inhibit NMDAR activity in the thalamus, so according to the chronic PCP model, they can disinhibit glutamatergic activity in this structure, leading to disinhibition of neurotransmission in the corticolimbothalamic circuit and in a longer perspective, in the receptor-adaptation mechanism, to hypofrontality [67]. Additionally, the decrease of glutamatergic activity in the thalamus and the hippocampus can additionally dysregulate the corticolimbothalamic circuitry. In the hippocampus, the structure belonging to the limbic system, all studied antipsychotic drugs decrease activity of NMDAR receptors, that implies a decrease of glutamatergic activity [66].  
The influence of antipsychotics on NMDAR composition has a different range. Olanzapine in rat archicortex inhibits the glutamatergic activity less than haloperidol. Hypothetically, this characteristic could make this drug favorable for cognition mechanisms related to the hippocampus. It was recently reported that olanzapine but not clozapine may increase the glutamate release in the mouse prefrontal cortex via inhibition of D-aspartate oxidase (DDO) activity [107]. One may also have some hope for the new antipsychotic drug brexpiprazole, that stimulates the glutamatergic activity in the animal prefrontal cortex in a dopamine receptor D1-dependent manner [108].  
We suggest that antipsychotics change the composition of NMDARs and decrease the NMDAR activity in the thalamus and hippocampus. As a consequence, the disturbances in the functioning of the corticolimbothalamic circuit occur, increasing or maintaining the present hypofrontality in patients who suffer from schizophrenia and take antipsychotic medication. Our NMDAR model of drug-induced hypofrontality suggests that chronic antipsychotic treatment of schizophrenia can dysregulate components of the corticolimbothalamic circuit and can affect negatively the cognitive functioning of patients. The hypothesis explains in part the incomplete effectiveness of antipsychotic drugs towards cognitive disturbances in schizophrenia, reviewed in [89].  
The limitation, which we see, is that we did not explore all the elements of the corticolimbothalamic circuit. Our results are limited to densitometric analysis of expression of NMRA-Rsubunits in brain slices, processed immunohistochemistry, without checking the mRNA transcription. We also did not assess the global expression of NMDAR proteins in the brain structures. We are also aware of the general limitations of translational science when animal results are tried to refer to humans' diseases, which we do in the conclusions.