D2 Mesolimbic Blockade — MRCPsych Paper B MCQ
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Correct answer: E — D2 receptor antagonism in the mesolimbic pathway
D2 receptor antagonism in the mesolimbic pathway is the standard mechanism used to explain improvement in positive psychotic symptoms, which are associated with excessive mesolimbic dopaminergic signalling. For dopamine-antagonist antipsychotics, therapeutic response is generally associated with substantial D2 occupancy, although excessive occupancy increases extrapyramidal adverse effects. Dopamine partial agonists such as aripiprazole require separate pharmacological description and should not simply be called D2 antagonists. 5-HT2A antagonism contributes to the receptor profile of several second-generation drugs but is not the principal shared mechanism for positive symptoms. Alpha-1 antagonism mainly causes postural hypotension and sedation. GABA-A agonism is not a standard antipsychotic mechanism, while NMDA antagonism can produce or exacerbate psychotic symptoms.
Reference: Royal College of Psychiatrists, Report CR190, The risks and benefits of high-dose antipsychotic medication, sections 'The pharmacological basis for high-dose antipsychotic prescribing' and 'Acute psychotic episode', revised 2023. https://www.rcpsych.ac.uk/usefulresources/publications/collegereports/cr/cr190.aspx