This video describes the 4 dopamine pathways relevant to the mechanism of action and adverse effects of antipsychotic drugs.
- General overview of dopaminergic pathways
- Mesolimbic pathway & positive symptoms of schizophrenia
- Mesocortical pathway: negative & cognitive symptoms
- Nigrostriatal pathway & EPS
- Tuberoinfundibular pathway & prolactin release
This image shows an integration of the four dopamine pathways I’ll be talking about. It’s essential that we learn about dopamine projections before studying how antipsychotics modify dopaminergic neurotransmission.
By blocking these pathways antipsychotics can produce both therapeutic and adverse effects.
The four pathways relevant to the pharmacology of antipsychotics in the treatment of schizophrenia are:
- The mesolimbic pathway (positive symptoms)
- The mesocortical pathway (negative symptoms)
- The nigrostriatal pathway (extrapyramidal symptoms and tardive dyskinesia)
- The tuberoinfundibular pathway (hyperprolactinemia)
As I just said, the mesolimbic pathway is relevant to positive symptoms of schizophrenia.
o This pathway is made up of projections from the ventral tegmental area that innervate many forebrain areas, the most important is the nucleus accumbens.
o Research suggests this system plays a key and complex role in motivation, emotions, reward and positive symptoms of schizophrenia.
o D2 antagonists reduce positive symptoms of schizophrenia. All antipsychotic drugs have the ability to reduce dopaminergic neurotransmission.
A number of investigators propose that negative and cognitive symptoms of schizophrenia are associated with hypofunction of the mesocortical pathway.
o This tract is made up of dopaminergic neurons that project from the ventral tegmental area to the prefrontal cortex.
oThe mesocortical pathway is thought to be relevant to the physiology of:
o Cognition and executive function (dorsolateral prefrontal cortex)
o Emotions and affect (ventromedial prefrontal cortex)
o As I just mentioned, hypofunction of the mesocortical pathway might be related to cognitive and negative symptoms of schizophrenia.
- The nigrostriatal system contains about 80% of the brain’s dopamine. This tract projects from cell bodies in the pars compacta of the substantia nigra to terminals that innervate the striatum (caudate and putamen).
- This pathway is involved in motor planning, dopaminergic neurons stimulate purposeful movement.
- D2 antagonism induces extrapyramidal symptoms. This is the case of first generation antipsychotics, high-potency D2 antagonists such as haloperidol frecuently cause pseudoparkinsonism.
Regarding anatomical considerations, this tract consists of dopaminergic projections from the hypothalamus (more specifically the arcuate and periventricular nuclei) to the infundibular region, also in the hypothalamus (or median eminence).
Dopamine is released into the portal circulation connecting the median eminence with the anterior pituitary gland.
This is very important, the role of dopamine release in the tuberoinfundibular pathway is to tonically inhibit prolactin release.
The main implication of this is that blockade of D2 receptors by drugs such as antipsychotics increases prolactin levels. The clinical consequences of hyperprolactinemia are discussed in other videos.
- Hyperactivation from the VTA to limbic areas might be related to positive symptoms of schizophrenia.
- Hypofunction of the mesocortical pathway might in part explain cognitive and negative symptoms of schizophrenia.
- D2 blockade of the nigrostriatal pathway can cause EPS.
- D2 blockade of the tuberoinfundibular pathway increases prolactin blood levels.
- Stahl, S. Stahl’s Essential Psychopharmacology: Neuroscientific Basis & Practical Applications. 3rd ed. Cambridge University Press, 2008.
- Golan D, Tashjian AH, Armstrong EJ. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2011.