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 3D Molecular Structure of Dopaminestructure 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.

Dopamine and Serotonin Pathways in the Brain

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.


Other Theories

Glutamate Theory

Glutamate, another neurotransmitter in abundance in the brain, is also thought to be involved in the action of antipsychotics. Drugs which act to block the NMDA receptor for glutamate such as ketamine, phencyclidine and dizocilpine produce effects which are very similar to the positive symptoms of schizophrenia. Low levels of glutamate receptors have also been found in schizophrenic patient's brains on postmortem. Glutamate can also modulate dopamine pathways, although exact mechanisms are still not understood.

Serotonin Theory

The theory that serotonin is involved in schizophrenia is based on the fact that LSD produces schizophrenia-like symptoms by activating serotonin receptors. Atypical antipsychotics are known to block serotonin receptors as well as dopamine receptors to varying degrees.

A table illustrating various properties of some antipsychotic drugs and their receptor affinities can be found on the Table of Antipsychotics page.

Related Links and References

Links to information regarding the molecular and anatomical functioning of antipsychotics:


Wikipedia pages on dopamine, the dopamine hypothesis of schizophrenia and antipsychotics, respectively:

http://en.wikipedia.org/wiki/Dopamine

http://en.wikipedia.org/wiki/Dopamine_hypothesis_of_schizophrenia

http://en.wikipedia.org/wiki/Antipsychotic

Some discussions and information on dopamine as a cause of schizophrenia, along with serotonin and glutamate also.


The British Journal of Psychiatry Article; Dopamine and Antipsychotic Drug Action Revisited:

http://bjp.rcpsych.org/cgi/content/full/181/4/271

In depth information and discussion on the effects of antipsychotic drugs on dopamine.


Williams College Antipsychotic Drugs page:

http://www.williams.edu/imput/synapse/pages/IIIB5.htm

Overview of the dopamine pathway and a nice animation of antipsychotic drugs' effects at the receptor.



Images courtesy of Wikimedia Commons under creative commons license, and Wikipedia from the US public domain, respectively:

http://commons.wikimedia.org/wiki/File:Dopamine-3d-CPK.png

http://en.wikipedia.org/wiki/Image:Dopamineseratonin.png

 


Fact

The dopamine theory of schizophrenia was proposed by Carlsson, who was awarded a Nobel prize in 2000 for his efforts.


Useless Fact

Dopamine is partly responsible for fruit browning when cut and exposed to air. An enzyme in bananas uses dopamine along with oxygen and other factors. This enzyme is part of a pathway ultimately leading to the formation of the pigment melanin, which has a brown colour.