# NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality
## 3 Expression of NMDA Receptor Subunits in the Rat Brain after Antipsychotic Treatment
### Thalamus, Hypothalamus, and Neocortex  
The functional profile of the thalamus goes far beyond the classical sphere of the central sensory pathways control. This complex brain structure affects almost all aspects of higher mental processes [93; 94]. Several thalamic disturbances are also present in the course of schizophrenia [95; 96; 97; 98; 99]. They are probably associated with the NMDAR hypofunction [100; 101]. Targeted microinjection of NMDA inhibitors into the rat thalamus causes cognitive deficits [102], that may support this hypothesis. Olanzapine, clozapine, and haloperidol decrease NMDAR expression in the rat thalamus [67], as shown in Figure 5, suggesting that long-term treatment with antipsychotic drugs can reduce the glutamate transmission in this structure, as shown in Figure 6. There could be two consequences of that finding. The decrease of activity of NMDARs can produce a decrease of the glutamatergic activity in the thalamus, as well as inhibit an activity of the GABA-ergic interneurons, producing disinhibition in the prefrontal cortex. Both consequences can significantly impair the functioning of a corticolimbothalamic circuit, as shown in Figure 7.  
Figure 5: The influence of chronic neuroleptic administration on NMDA receptor subunits’ expression in thalamus, hypothalamus, and cortex in rats. Arrows indicate the subunit expression decrease or increase by 0–25% (\(\downarrow\)), 2–50% (\(\downarrow\downarrow\)), 51–75% (\(\downarrow\downarrow\downarrow\)), and 76–100% (\(\downarrow\downarrow\downarrow\downarrow\)). Figure 6: The influence of chronic neuroleptic administration on glutamatergic activity in thalamus, hypothalamus, and cortex in rats. A number of arrows indicate the neuroleptic’s potential to decrease or increase 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). * statistically non-significant. Results of expression of NMDAR subunits in the hypothalamus, as shown in Figure 5, turn out to be surprising [67]. It is only the rat brain structure where we observed an increase of NR1 expression after a long-term administration of olanzapine or haloperidol. That means that the long-term action of both olanzapine and haloperidol induces the increase of the number of NMDARs in the hypothalamus. Moreover, clozapine and haloperidol, decreasing NR2A subunit expression, could also increase the NMDAR activity. Similar results were obtained by [PERSON] et al. (1997) after three weeks of haloperidol or clozapine administration [77]. In their study, the neuroleptics decreased the expression of NR2A subunits in the hypothalamus. Concluding, all three antipsychotic drugs can increase the glutamatergic activity in the hypothalamus. We are aware that the hypothalamus is not generally considered as the structure directly involved in the pathogenesis of cognitive dysfunction and hypofrontality. As the whole brain region, it is not a part of corticolimbothalamic loop, however it may be important in the analysis of some adverse effects of antipsychotics, e.g., neuroleptic-induced food-intake promoting action of neuropeptide Y (NPY) and orexins (OXs), which seem to depend on the hypothalamic NMDAR activity of NMDA [103, 104]. Thus, an increase in the NMDAR expression as well as NPY and OXs in the hypothalamic nuclei [105], may be one of several causes of the well-known unwanted metabolic disturbances after treatment with antipsychotics. Figure 7: An effect of antipsychotics on cortical-subcortical circuits in the hypothetical drug-induced mechanism of hypofrontality. The prefrontal cortex sends excitatory glutamatergic outputs to the limbic system (hippocampal formation), its GABA—ergic inhibitory projections are running to the thalamus, from where glutamatergic innervation goes back to the cortex. Some hippocampal outputs target also ventral striatum, ventral pallidum, substantia nigra, and the ventral tegmental area (VTA).