What is the main MOA for Phenothiazines such as Chlorpromazine and Thioridazine?

• A. Dopamine receptor antagonist
• B. Serotonin receptor antagonist
• C. GABA agonist
• D. Acetylcholine receptor antagonist

Answer: (A)

Phenothiazines such as chlorpromazine and thioridazine work primarily by blocking dopamine D2 receptors in the brain. This antagonism reduces dopaminergic signaling in pathways that drive psychotic symptoms, especially the mesolimbic pathway, which helps lessen delusions and hallucinations. Blocking D2 receptors in the tuberoinfundibular pathway also lifts the usual dopamine inhibition of prolactin release, leading to potential hyperprolactinemia. While these drugs can affect other receptors (histamine, muscarinic, alpha-adrenergic) and cause various side effects like sedation or orthostatic hypotension, the defining action for their antipsychotic effect is D2 receptor antagonism. This contrasts with newer agents that target additional receptors such as 5-HT2A, which is more characteristic of atypical antipsychotics.