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 alpha(2)-adrenoceptor antagonist, idazoxan, or the D-1 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 alpha(2) 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 alpha(2) adrenoceptors and D-1 dopamine receptors in the PFC. These receptor actions likely contribute to their therapeutic effects in the treatment of attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(10):1011-1023.