# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 3 Expression of NMDA Receptor Subunits in the Rat Brain after Antipsychotic Treatment
### Hippocampal Formation
We observed that clozapine and olanzapine decrease NR2A subunit expression in the CA1 region of the hippocampus, with no influence on a number of NR2B subunits, so clozapine and olanzapine can increase the receptor activity by changing the subunit composition in NMDARs. The lack of a significant influence of olanzapine on the expression of NR2B subunits together with the decrease of NR2A, one can explain an advantageous action of olanzapine on visual-spatial learning versus clozapine and haloperidol in schizophrenia-suffering people [89]. A similar influence of clozapine and olanzapine on the expression of NMDAR subunits shows its ability to enhance the glutamatergic activity in CA1 and improve memory mechanisms. In turn, haloperidol decreases NR2B expression in rats, as shown in Figure 2. That finding can explain how olanzapine can exert preferential influence on memory, compared with haloperidol [89]. In the gyrus dentatus, haloperidol decreases expression of NR2B subunits and olanzapine decreases expression of NR2B and NR2A subunits. The results are in accordance with [PERSON] et al. (2002), who did not observe changes in the production of mRNA for NR1 subunits in the rat brain structure [84]. Change of composition of NMDAR subunits in the gyrus dentatus is an interesting finding when referred to the study by [PERSON] et al. (2007) [90]. Administration of NMDAR antagonist MK-801 decreases neurogenesis in mice gyrus dentatus, and clozapine but not haloperidol counteracts this effect. That means that the decrease of glutamatergic activity in the gyrus dentatus can decrease neurogenesis. In our study, clozapine, opposite to haloperidol and olanzapine, does not change the expression of NMDAR subunits in the gyrus dentatus, as shown in Figure 2, that implies no effect of clozapine on glutamatergic activity. Haloperidol, decreasing the expression of NR2B subunits, can decrease the NMDAR activity, inhibiting neurogenesis and worsening schizophrenia symptoms in humans. Nevertheless, some studies report that long-term treatment (28 days) with haloperidol stimulated DCX-positive neuroblast formation in the rat subventricular zone (SVZ) [91] and supported adult neurogenesis in the gyrus dentatus [92]. The decrease of expression of NMDAR subunits, induced by haloperidol, can relate to functional antagonism between receptors D2 and NMDA and post-translational alterations of protein subunits of NMDARs [78; 85]. The decrease of NMDAR expression can also result from the interaction between receptors D1 and NMDA. It was shown in cell cultures of striatum cells that an increase of NMDARactivity correlates with an increase of D1 receptor density. It was also proved that long-term blocking of D2 receptors decreases the expression of receptors' D1, that in turn is a reason for the decrease in production of BDNF and reduction of neurogenesis. A conclusion is that the increase of NMDAR activity, with the increase of D1 receptor density, plays a neuroprotective role [7]. According to [PERSON] et al. (2007), inhibition of neurogenesis is one of the elements of complex pathogenesis of schizophrenia in humans [90].