Amphetamine monoamine release — MRCPsych Paper A MCQ

Correct answer: B — DAT substrate action, VMAT2-related vesicular redistribution and reverse DAT-mediated dopamine efflux

Amphetamine acts as a transporter substrate rather than solely as an uptake blocker. It enters dopaminergic terminals through DAT, disrupts VMAT2-dependent vesicular storage and raises cytosolic dopamine. Dopamine is then released non-exocytotically through reverse DAT transport, increasing extracellular concentrations and contributing to euphoria, increased speech and insomnia. Option A more closely describes a pure uptake inhibitor such as cocaine or methylphenidate and specifically omits amphetamine-associated efflux. MAO inhibition is not amphetamine's principal acute mechanism. Sustained VMAT2 blockade, as with vesicular monoamine-depleting drugs, eventually reduces releasable stores rather than producing this characteristic stimulant response. Amphetamine also does not act principally as a direct postsynaptic D1 agonist.

Reference: Dutta CN et al. Neuroprotection in late life attention-deficit/hyperactivity disorder: A review of pharmacotherapy and phenotype across the lifespan, Figure 2: mechanisms of action for stimulant drugs. Frontiers in Human Neuroscience, 2022. https://pubmed.ncbi.nlm.nih.gov/19199083/