When multiple genes and environmental factors are combined, one can be begin to suffer from psychosis. The current theory is that psychotic disorders are triggered by an abnormal increase in dopaminergic activity in the brain. Dopamine likely works on neural circuits that are involved in filtering the information that may be processed in the prefrontal cortex. If too much dopamine is active in the brain, this process may be affected. Changes in dopaminergic activity can negatively affect cognitive domains that concern the prefrontal cortex, like working memory, cognitive flexibility, attention, and interference control. Problems with each of these domains are present in people suffering from schizofrenia and other psychotic disorders.

Luckily, antipsychotics are capable of binding to many types of dopamine receptors (D1, D2, D3, and D4). Antipsychotic molecular structures allow these drugs to bind to the receptors more strongly than dopamine does.  However, they cannot activate the protein that causes a postsynaptic response, which is what is trying to be avoided. With the antipsychotic in the way, dopamine can no longer bind to the receptor and, therefore, cannot open the sodium ion channel. In this way, antipsychotics reduce dopaminergic activity, and therefore reduce the symptoms of psychosis.

Typical antipsychotics are mainly attracted to D2 receptors. By binding to D2, they help the patient with their psychosis, but also cause problems. This is because D2 receptors have been found on more than just the post-synaptic membrane. As a result, antipsychotics also reduce dopaminergic activity in other pathways that are not related to psychotic symptoms. Typical antipsychotics cause side effects for this reason. Atypical antipsychotics, on the other hand, do not bind as well with D2, but instead, are highly attracted to D3 and D4. These two types of dopamine receptors are only expressed on neurons of the limbic system and cerebral cortex. This means that atypical drugs almost exclusively affect the pathology of psychosis and, therefore, cause fewer side effects.

Most of the six chemical groups (discussed in this blog post) are known to bind to specific dopamine receptors. For example, the typical  phenothiazines and thioxanthenes are known to bind to D1 and D2 receptors. Diphenylbutylpiperidines, on the other hand, have a mysterious mechanism. Still, these derivatives definitely slow dopaminergic activity. Clozapine (a type of dibenzodiazepine) reduces dopaminergic activity without blockage, but antagonizes serotonin receptors 5-HT2A and 5-HT2C.

In order to reduce the symptoms of psychosis, dopaminergic activity in the brain must first be reduced. Because of their special structures, antipsychotics are capable of doing this.

By Mariel Hohmann


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