# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 3 Expression of NMDA Receptor Subunits in the Rat Brain after Antipsychotic Treatment  
### Hippocampal Formation  
The hippocampal formation, a part of the _archicortex_, plays a key role in the most widely understood cognitive mechanisms [68; 69; 70] and its numerous dysfunctions are often described in schizophrenia [71; 72; 73; 74]. In hippocampal regions CA1 and CA2, all tested drugs decrease expression of the NR1 subunit, that indicates that olanzapine, clozapine, and haloperidol decrease the number of NMDARs in those structures, as shown in Figure 2[66]. In the CA3 area, haloperidol and olanzapine but not clozapine, decrease NMDAR numbers, as shown in Figure 2. The data suggest that chronic administration of antipsychotics can decrease the glutamatergic activity in the hippocampus, as shown in Figure 3. [PERSON] et al. (2003) in a similar study found that both haloperidol and clozapine given to rats for two weeks decrease expression of the NR2B subunit in the hippocampus [75]. In that study, results were the same after four weeks, which indicates the durability of the changes of NR2B subunit expression in long-term drug administration. [PERSON] et al. (2003) showed that both haloperidol and clozapine, given for 6 months, reduce expression of NR2A subunits in the CA1 hippocampal region [76]. In the study by [PERSON] et al. (1997), one dose of haloperidol evoked an increase of expression of mRNA for subunits NR2A and NR2B, but the effect withdrew after 21 days of continuous administration of the antipsychotic [77]. We showed the decrease of NR2A subunits in the CA1 hippocampal region after the long-term administration of both clozapine and olanzapine, but not with haloperidol. That means that in one area of the brain, antipsychotic drugs can differently influence the expression of NMDAR subunits. The difference can also be explained with the length of a period in which the antipsychotic is given. For example, in our studies, clozapine after four weeks exerted the same effect as that after six months in the study by [PERSON] et al. [76]. It is not excluded that also haloperidol given longer than one month could decrease the expression of NR2A subunits in the CA1 region of the hippocampus. [PERSON] et al. (2003) in their study showed results similar to ours with olanzapine--they found that after 30 days it decreases the number of NMDARs in the CA1 and CA3 regions [78]. Results from the above-mentioned studies are summarized in Figure 4. We propose that the effect of antipsychoticshetics in the hippocampus is related to the change of composition of NMDAR subunits that cause the decrease of glutamatergic activity. Our results are interesting when thinking about a reduction of the volume of the hippocampus in schizophrenia [79] and involvement of the hippocampus in cognitive deficits and pathogenesis of schizophrenia [78]. Much more NMDARs are located in a rat's CA1 region, compared with CA3 [78]. In humans, the CA1 region plays a significant role in the long-term potentiation (LTP), which consists of a key molecular mechanism of memory [80]. Perhaps the antipsychotic-induced decrease of glutamatergic activity in the CA1 hippocampal region is responsible for the incomplete treatment effect of cognitive deficits in schizophrenia. Damping of glutamatergic activity in the hippocampus by antipsychotic drugs could interfere with mechanisms of learning and memorizing. Figure 3: The influence of chronic antipsychotic drug administration on glutamatergic activity in CA1, CA2, and CA3 hippocampus regions and in gyrus dentatus in rats. A number of arrows indicate the neuroleptic’s potential to decrease the glutamatergic activity, resulting from the summation of NR1 expression, and proportion of NR2A to NR2B expression (an arrow was added when NR2B expression prevailed, and subtracted when NR2A expression prevailed). Figure 2: The influence of chronic antipsychotic drug administration on NMDA receptor subunits’ expression in CA1, CA2, and CA3 hippocampus regions and in gyrus dentatus in rats.