# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 3 Expression of NMDA Receptor Subunits in the Rat Brain after Antipsychotic Treatment
### Hippocampal Formation
Arrows indicate the subunit expression decrease by 0–25% (\(\downarrow\)), 26–50% (\(\downarrow\downarrow\)), 51–75% (\(\downarrow\downarrow\downarrow\)), and 76–100% (\(\downarrow\downarrow\downarrow\downarrow\)). The decrease of NMDARs in the CA1 region can be explained by a direct influence of drugs on the receptor complex, although it seems that both olanzapine [78] and clozapine [19] have no affinity towards NMDARs. However, it is suggested that clozapine may modulate dopaminergic neuron activity in the rat ventral tegmental area (VTA) via binding to the NMDAR glycine sites [81]. Clozapine may also act as Mg\({}^{2+}\) and voltage independent NMDAR channel blocker [82]. Haloperidol exerts an antagonistic activity against NMDARs, binding with a specific allosteric site of NR2B [83]. Although, the inhibition of NMDAR activity with haloperidol requires much higher drug concentration at the receptor, compared with regular concentrations, obtained with standard doses of haloperidol when used in the treatment of schizophrenia [83]. Thus, it seems the direct blockade of NMDARs by haloperidol has no practical importance [83]. The mechanism of action of haloperidol can be non-related to the transcription of genes. Our data indicate that haloperidol does not increase expression of NR1 subunits in the hippocampal CA1 region. It is so, although haloperidol can increase the transcription of NR1 genes in this area [84]. In our understanding, the observed decrease of NMDA expression in cell membranes  
Figure 4: A comparative effect of second-generation antipsychotics on the NMDA receptor subunits expression in the rat brain. A comparative juxtaposition of the main studies in the field depicting brain structures with decreased (red) or increased (blue) NMDR subunit expression. Changes statistically not significant or no data in gray. Hi; hippocampus, FC; frontal cortex, PC; parietal cortex, Th; thalamus, Hy; hypothalamus, S; striatum, NAc; nucleus accumbens, Ch; cerebellum. is induced rather through interaction between glutamatergic, dopaminergic, and serotoninergic neurotransmission systems. The dopaminergic and serotoninergic systems are influenced by olanzapine and clozapine, when haloperidol blocks only the dopaminergic receptors (mainly type 2, D2). Indirect evidence that the serotoninergic system is involved in NMDAR expression is the participation of the 2A type of serotoninergic receptor in the mechanism of action of PCP and ketamine. Moreover, D2 and NMDARs can be in functional antagonism [78]. Chronic D2 blocking with antipsychotics and their up-regulation decreases expression of NMDARs [85]. Through that mechanism, an antipsychotic drug can decrease excessive dopaminergic activity in the CA1 region of the hippocampus [86] and also decrease stimulation in glutamatergic projections to the limbic system and brain cortex [78]. For that reason, the changes of expression of NMDARs can be linked with a chronic blocking of 5-HT2A and D2. Moreover, the receptor blockade may induce post-translational alterations in NMDAR subunits and in this way modulate their expression in cell membranes [78]. In our experiments, clozapine and olanzapine did not influence the expression of NR2B subunit (clozapine in C1 and C3, and olanzapine in C1) as shown in Figure 2. The subunit in humans regulates NMDAR activity and its increase is associated with higher receptor activity [87]. According to [PERSON] et al. (2010), the most important NMDAR pathology in schizophrenia refers to receptors containing the NR2B subunits [55]. The NR2B subunit is involved in LTP and better synaptic transmission [88]. Decreased numbers of NR2B in receptor composition is linked to problems with learning and memory [55]. When NR2A subunits dominate in NMDAR composition, synaptic plasticity is decreased [87]. A preponderance of NR2B in NMDARs can result from its higher expression or a decrease of NR2A subunit numbers.