Circuit substrates of ADHD drugs

Easton et al has used small animal pharmacological (ph) MRI on rats after administering a number of different ADHD drugs (methylphenidate, atomoxetine, guanfacine, and d-amphetamine) to determine their effects on various brain regions. Previous studies have performed immunohistochemical studies in the rat on the levels of dopamine and noradrenaline transporter (DAT and NET, respectively). The result of their hard work is this fascinating table:

ADHD drug regionsA negative sign indicates that the drugs downregulated activity in the region and a plus sign indicates that the drug upregulated activity in that region, in so far as BOLD contrasts indicated changes in neuron activity. These procedures compared the effects of these drugs on healthy adult rats to the effects of saline solution. One consistent positive region of effect is the nucleus accumbens, a dopaminergic nerve terminal area (see its high levels of DAT) which is often implicated in the deficits found in ADHD. The most persistent negative BOLD effect occured in the caudate putamen. Methylphenidate is known to block dopamine transporters due to its high binding affinity, and usual doses usually competitively occupy ~ 50% of the transporters. This likely leads to a down-tuning of post-synapse dopamine-related neuronal events in regions like the caudate putamen. The search for the mechanism of ADHD drugs, the most commonly prescribed and most highly abused psychostimulants, continues.

Reference

Easton N, et al. 2009 Mapping the central effects of methylphenidate in the rat using pharmacological MRI BOLD contrast. Neuropharmacology, Article in Press. doi:10.1016/j.neuropharm.2009.08.018.