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The Four Dopamine Pathways

Truthometer

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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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The mesolimbic pathway is relevant to positive symptoms of schizophrenia [1].

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.

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 Hypofunction of the mesocortical pathway might be related to cognitive and negative symptoms of schizophrenia [2].




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.

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.
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.

Aripriprazole - being a partial agonist - does not cause elevations in prolactin levels, unlike dopamine antagonist antipsychotics.
 
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