How Do They Work? :: Antipsychotic Drugs

How Do They Work?

Antipsychotics, regardless of whether typical or atypical, all have one feature in common; they block dopamine receptors in the brain. This page outlines what dopamine and the dopamine pathway is, how antipsychotics reduce dopamine levels, and also the action of serotonin, another target for atypical antipsychotics.

Dopamine

Dopamine is a chemical released by neurons in the brain which acts as a transmitter to signal to other cells, hence it is termed a neurotransmitter. The 3D molecular

structure of dopamine is illustrated to the right. Dopamine acts by binding to five different types of dopamine receptor on the surface of cells, named D₁ through to D₅. D₁ and D₅ dopamine receptors make up one classification (D₁-like) and D₂ D₃ and D₄ belong to the other classification (D₂-like). When dopamine binds to its receptor on a neuron, it sets off a series of events which leads to activation of the neuron and production of an action potential, which can then travel down the neuron and produce the same events in the neighbouring neuron.

It has been demonstrated that around 80% of the D₂-like receptors need to blocked in order to produce an antipsychotic effect. Older (typical) antipsychotics tend to be selective of D₂-receptors over D₁. Newer atypical drugs are highly D₂ selective, and some are not selective for either, but show selectivity for D₄-receptors, such as clozapine. Upon reaching the dopamine neurons in the brain, antipsychotic drugs compete with dopamine for binding to the dopamine receptors. Once bound, the drugs prevent dopamine binding and so reduce the excess dopamine's effects.

Anatomy

Dopamine utilising neurons are found in specific regions of the brain, in particular the mesolimbic, mesocortical, tuberoinfundibular and nigrostriatal pathways:

• The Mesolimbic Pathway starts in the ventral tegmental area (VTA), and connects to the hippocampus and amygdala via the nucleus accumbens. It is involved in reward and pleasure or motivation, and also the positive symptoms of schizophrenia.
• The Mesocortical Pathway connects the VTA to the frontal cortex. It is involved in motivation and emotional response, and also believed to be responsible for the negative symptoms of schizophrenia.
• The Nigrostriatal Pathway connects the substantia nigra to the striatum. It is involved in the production of movement.

These pathways are highlighted in the illustration below in blue.

The reduced dopamine due to antipsychotic drugs in the mesolimbic and mesocortical pathways is suggested to be responsible for reducing psychosis. The reduced dopamine in the nigrostriatal pathway is believed to be responsible for unwanted side effects, particularly movement problems. Haloperidol, a typical antipsychotic, doesnt show any specificity towards any dopamine pathway, and so has some serious side effects affecting movement. However, Clozapine, an atypical antipsychotic specifically targets VTA neurons and so doesnt have any movement side effects.

The fourth dopamine pathway; the tuberoinfundibular pathway can produce some unwanted hormonal effects. Dopamine released in this pathway leads to the increase of prolactin levels. Prolactin is a hormone which can cause breast swelling, pain and lactation, even in males. It can also cause visual problems, headaches and sexual dysfunction. There is more about this subject on the Side Effects page.