Abstract
BackgroundMethylphenidate (MPH) is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet the mechanisms underlying its therapeutic actions remain unclear. Recent studies have identified an oral, MPH dose regimen which when given to rats produces drug plasma levels similar to those measured in humans. The current study examined the effects of these low, orally-administered doses of MPH in rats performing a delayed alternation task dependent on prefrontal cortex (PFC), a brain region that is dysfunctional in ADHD, and is highly sensitive to levels of catecholamines. The receptor mechanisms underlying the enhancing effects of MPH were explored by challenging the MPH response with the noradrenergic α2 adrenoceptor antagonist, idazoxan, and the dopamine D1 antagonist, SCH23390.ResultsMPH produced an inverted U dose response whereby moderate doses (1.0–2.0 mg/kg, p.o.) significantly improved delayed alternation performance, while higher doses (2.0–3.0 mg/kg, p.o.) produced perseverative errors in many animals. The enhancing effects of MPH were blocked by co-administration of either the α2 adrenoceptor antagonist, idazoxan, or the dopamine D1 antagonist, SCH23390, in doses that had no effect on their own.ConclusionThe administration of low, oral doses of MPH to rats has effects on PFC cognitive function similar to those seen in humans and patients with ADHD. The rat can thus be used as a model for examination of neural mechanisms underlying the therapeutic effects of MPH on executive functions in humans. The efficacy of idazoxan and SCH23390 in reversing the beneficial effects of MPH indicate that both noradrenergic α2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.
Highlights
Methylphenidate (MPH) is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet the mechanisms underlying its therapeutic actions remain unclear
Converging evidence has demonstrated that ADHD symptoms arise from dysregulation of prefrontal cortical (PFC)/striatal and cerebellar circuits
MPH dose/response: Effects on delayed alternation performance The effects of an acute, oral dose of MPH were examined over the dose range found to produce drug plasma levels in rats similar to clinical use in ADHD (0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg, oral administration 30 min before testing)
Summary
Methylphenidate (MPH) is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet the mechanisms underlying its therapeutic actions remain unclear. The current study examined the effects of these low, orally-administered doses of MPH in rats performing a delayed alternation task dependent on prefrontal cortex (PFC), a brain region that is dysfunctional in ADHD, and is highly sensitive to levels of catecholamines. Methylphenidate (MPH) is a leading treatment for Attention Deficit Hyperactivity Disorder (ADHD). This compound has been used for decades, the neural mechanisms underlying MPH's therapeutic actions are still unknown. Imaging studies have shown that MPH produces more efficient PFC function in both ADHD patients [6] and control subjects [7], consistent with this view
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