D2 antagonist

• If BBB-crossing:
• Mesolimbic blockade → ↓ aberrant salience/positive symptoms
• Nigrostriatal blockade → EPS
• Tuberoinfundibular blockade → ↑ prolactin
• Chemoreceptor trigger-zone blockade → antiemetic effect

D2 antagonist (1/2)

• Primary mechanism of antipsychotic efficacy for positive symptoms – mesolimbic D2 blockade → ↓ aberrant salience attribution (e.g., exaggerated threat assignment)
• Tranquilization without sedation
• Cortical effect – mesocortical D2 blockade
• ➔ may worsen negative/cognitive symptoms
• Antimanic – dampens dopaminergic hyperactivity in mesolimbic and mesocortical circuits
• ➔ prokinetic also – D2 blockade in myenteric plexus → disinhibits ACh release → ↑ gastric emptying and duodenal peristalsis
• Extrapyramidal symptoms (EPS) – D2 blockade in nigrostriatal pathway → relative acetylcholine excess
• Prolactin elevation – tuberoinfundibular D2 blockade → removal of DA’s tonic inhibition of pituitary lactotrophs

D2 antagonist (2/2)

• Alternative splicing of the DRD2 gene produces two isoforms: D2S (short) and D2L (long)
• ➔ high efficacy in schizophrenia
• ➔ atypical clinical profile despite minimal 5-HT2A blockade D2S isoform-preferring D2 blocker

Drugs with this mechanism (59)

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