Methylphenidate and Atomoxetine Enhance Prefrontal Function Through α₂-Adrenergic and Dopamine D₁ Receptors

Objective

This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels.

Method

Monkeys performed a working memory task after administration of a wide range of MPH or ATM doses. The optimal doses were challenged with the α₂-adrenoceptor antagonist, idazoxan, or the D₁ dopamine receptor antagonist, SCH23390 (SCH). In a parallel physiology study, neurons were recorded from the dorsolateral PFC of a monkey performing a working memory task. ATM, SCH, or the α₂ antagonist, yohimbine, were applied to the neurons by iontophoresis.

Results

MPH and ATM generally produced inverted-U dose-response curves, with improvement occurring at moderate doses, but not at higher doses. The beneficial effects of these drugs were blocked by idazoxan or SCH. At the cellular level, ATM produced an inverted-U dose-response effect on memory-related firing, enhancing firing for preferred directions (increasing “signals”) and decreasing firing for the nonpreferred directions (decreasing “noise”). The increase in persistent firing for the preferred direction was blocked by yohimbine, whereas the suppression of firing for the nonpreferred directions was blocked by SCH.

Conclusions

Optimal doses of MPH or ATM improved PFC cognitive function in monkeys. These enhancing effects appeared to involve indirect stimulation of α₂ adrenoceptors and D₁ dopamine receptors in the PFC. These receptor actions likely contribute to their therapeutic effects in the treatment of attention-deficit/hyperactivity disorder.

Key Words: methylphenidate, atomoxetine, attention-deficit/hyperactivity disorder, norepinephrine, dopamine