D2 antagonist

D2 dopamine receptor antagonist

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

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