You can watch the video tutorial here

Author: Flavio Guzman, MD

Psychiatrist
Pharmacology Department
University of Mendoza
Argentina

In this video I will introduce dopamine pathways and their physiology relevant to antipsychotics
pharmacology.
The learning objective of this presentation is to understand basic concepts of dopaminergic
pathways and their relevance to antipsychotic effects.

Let’s start by outlining the dopaminergic pathways.

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)

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 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 dopamine pathway is related to

neurological effects caused by D2 antagonists.
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.

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 Dopaminergic projections in the tuberoinfundibular
pathway influence prolactin release.
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.