Scientists then sought to look for the causes of the negative symptoms of psychosis. Through research, the cognitive deficits of psychosis were found to correlate with a decline in DA receptors in the PFC, predominantly at D1 receptors (Brisch, 2014). It is believed that the negative symptoms of schizophrenia, for example, are caused by excessive pruning, or loss of brain volume in the PFC (Meyer, 2019). The positive symptoms are caused by the loss of top down (prefrontal) control of VTA (brainstem) dopamine neurons (Meyer, 2019). Since antipsychotics target the dopamine system, they are effectively treating the positive symptoms and are equally ineffective in treating the negative symptoms. This opened up the theory that not only were D2 receptors responsible for psychosis, but it is primarily due to an imbalance of D1 and D2 receptors in the PFC (Brisch, 2014). Furthermore, the D2 receptor, in disinhibition, was recognized to be main reason of promoting positive symptoms of psychosis while the D1 receptor, in disinhibition, was recognized to be the main reason of promoting negative symptoms (Brisch, 2014). In summary, the extreme chaotic release of DA in the brain of a patient suffering from psychosis, with emphasis on the PFC, was found to be a potential mediator in the development of psychotic symptoms.
There is more than one neurotransmitter involved with psychosis. As mentioned above, neuroleptic drugs work with D2 receptors, along with 5-HT2A. The hallucinogenic drug, LSD, exerts its effects by activating the 5-HT2A receptors as an agonist (Meyer, 2019). Due to this, atypical antipsychotics were developed to have a lower affinity for the D2 receptor and a higher affinity for the 5-HT2A receptor (Meyer, 2019). The blocking of 5-HT2A receptors by atypical antipsychotics was found to be just as useful as the neuroleptics, just with less severe side effects (Meyer, 2019). The specific D2 receptor occupancy of neuroleptics in the striatum interacts with the antagonistic effects of 5-HT2A receptors (Brisch, 2014).
In studies of psychosis, an increase in D2 receptor density can be found in high-affinity in specific neurotransmitter pathways such as those of glutamate, gamma-aminobutyric Acid (GABA), and acetylcholine (ACh) (Brisch, 2014). The presence of D1 receptors can be found in GABA interneurons as well, therefore if a drug affects GABA receptors, it subsequently affects DA receptors (Brisch, 2014). Similarly, certain D1 and D2 receptors cooperate with the major glutamate subtype receptor NMDA as a receptor mosaic (Brisch, 2014). GABA and glutamate are both known for regulating DA activity in the brain (Brisch, 2014). Furthermore, D2 receptor antagonists that can act as D1 receptor agonists, improve NMDA synaptic transmission (Brisch, 2014). In summary, to have an effective antipsychotic drug, DA must properly interact with other neurotransmitter pathways to get the desired effect.
