Methylphenidate, known commonly as Ritalin, is a central nervous system stimulant used mainly for ADHD, but also for narcolepsy. ADHD is caused by an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD-4), and/or the D2 receptor gene. It has also been found to affect the alpha-2A adrenergic receptor in the prefrontal cortex. This abnormality makes it harder for dopamine and norepinephrine to bind to the receptors. These receptors regulate attention, movement, and impulsivity so a defeciency in the regulation of those systems causes ADHD. Methylphenidate blocks the reuptake transporters of both dopamine and norepinephrine which prolongs their duration in the synapse so that they can bind more readily to the receptors. Since it works in the brain Methylphenidate crosses the blood brain barrier through diffusion. Norepinephrine similarly works but it is synthesized in the locus coeruleus where it is synthesized from dopamine by the enzyme dopamine beta-hydroxylase. Norepinephrine is then transported to the prefrontal cortex and released into the synapse when the neuron is stimulated and fires. Methylphenidate binds and blocks the sodium-dependent noradrenaline transporter which prevents the synaptic norepinephrine from re-entering the presynaptic neuron. Norepinephrine then binds to the Alpha-2A adrenergic receptor on the postsynaptic membrane. Alpha-2A adrenergic receptor activates the Gi coupled protein cascade which inhibits adenylate cyclace. This means adenylate cyclase cannot catalyze ATP into cAMP. The reduced cAMP isn't able to activate protein kinase A as much which causes a reduction neuronal excitability. Alpha-2A adrenergic receptor is associated with regulating and improving working memory. It is unknown how exactly this helps with ADHD, but it is speculated to help by regulating attention, movement, and impulsivity to a greater degree. Other dopamine and norepinephrine receptors are likely also involved, but the main receptors complicit in ADHD are the dopamine D4 receptor and the alpha-2A adrenergic receptor. This helps people with ADHD to sustain attention and working memory.

Methylphenidate Norepinephrine Reuptake Inhibitor Pathway References