19.02.4 Antipsychotic Mechanisms of Action

Antipsychotic drugs are potent dopamine D₂ receptor antagonists. D₂ autoreceptors control release of dopamine from presynaptic neurons. By blocking elevated ventral striatal dopamine release, antipsychotics ameliorate dopamine dysregulation. Animal studies have shown that antipsychotics initially increase (due to D₂ receptor autoreceptor blockade) and then decrease midbrain dopaminergic neuron activity in the substantia nigra and ventral tegmental area (containing dopaminergic cell bodies), and dopamine release in regions where dopamine cells project to, such as the ventral striatum and prefrontal cortex. This decreased dopaminergic activity occurs as D₂ receptors upregulate due to chronic blockade, and the time course of this increased receptor expression parallels the delayed therapeutic effect of the drugs.

The therapeutic effects of antipsychotics, as already mentioned, are thought to occur via the mesocortical/mesolimbic dopamine pathway (ventral tegmental area to prefrontal cortex and ventral striatum). The side effects commonly seen with antipsychotics are thought to occur through antagonism of the nigrostriatal pathway (substantia nigra to caudate/putamen), where movement disorders result, and the tuberoinfundibular pathway (hypothalamus to pituitary), which lead to endocrine abnormalities