A 9-year-old boy presents with inattention, impulsivity, and hyperactivity across school and home. He was started on methylphenidate. Which mechanism explains methylphenidate's therapeutic action in ADHD?

• A Stimulates post-synaptic D1 and D2 receptors directly
• B Increases dopamine and norepinephrine at the synapse by blocking their reuptake transporters (DAT and NET) in the prefrontal cortex and striatum ✓
• C Inhibits monoamine oxidase, increasing synaptic monoamine levels
• D Blocks alpha-2A adrenergic autoreceptors, increasing norepinephrine release

Explanation

Methylphenidate blocks dopamine transporter (DAT) and norepinephrine transporter (NET), preventing reuptake and increasing synaptic concentrations of dopamine and norepinephrine. In the prefrontal cortex (PFC), increased NE acting on α2A receptors and DA on D1 receptors strengthens 'top-down' cognitive control networks underlying attention and impulse inhibition. In the striatum, DA enhancement modulates reward circuits. Alpha-2A adrenergic agonists (guanfacine, clonidine) work via a different mechanism — direct post-synaptic α2A stimulation in PFC — and are used as non-stimulant alternatives in ADHD.

Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.

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