Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder

Abstract

BACKGROUND: Methylphenidate (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 alpha2 adrenoceptor antagonist, idazoxan, and the dopamine D1 antagonist, SCH23390. RESULTS: MPH 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 alpha2 adrenoceptor antagonist, idazoxan, or the dopamine D1 antagonist, SCH23390, in doses that had no effect on their own. CONCLUSION: The 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 alpha2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.

Figure 1

The effects of oral administration of methylphenidate (MPH) on delayed alternation performance in male rats. A. Representative dose/response curves from two individual rats. Results represent percent correct on the delayed alternation task following MPH administration. For most rats, a lower dose (1.0–2.0 mg/kg, p.o. 30 min) was found to improve performance, while higher doses often impaired performance (1.5–3.0 mg/kg). Rats showed individual differences in dose sensitivity. B. An optimal dose of MPH was found for all rats which significantly improved delayed alternation performance. Results represent mean ± S.E.M. percent correct on the delayed alternation task. VEH = cracker vehicle; MPH = optimal dose of methylphenidate (1.0–2.0 mg/kg); ** significantly different from VEH p = 0.002. C. Higher doses of MPH impaired performance and produced a perseverative pattern of errors. Perseveration was assessed by the greatest number of consecutive entries into a single arm of the T maze. Results represent mean ± S.E.M. number of consecutive entries. VEH = cracker vehicle; MPH = impairing dose of methylphenidate (1.5–3.0 mg/kg); * significantly different from VEH p = 0.046.

Figure 2

The enhancing effects of methylphenidate were blocked by co-administration of the α2 adrenoceptor antagonist, idazoxan at a dose which had no effect on its own. Results represent mean ± S.E.M. percent correct on the delayed alternation task. VEH = cracker vehicle; MPH = optimal dose of methylphenidate (1.0–2.0 mg/kg); IDA = idazoxan (0.1 mg/kg); ** significantly different from VEH, p = 0.002; † significantly different from MPH, p = 0.003.

Figure 3

The enhancing effects of methylphenidate were blocked by co-administration of the dopamine D1 receptor antagonist, SCH23390 at doses which had no effect on their own. Results represent mean ± S.E.M. percent correct on the delayed alternation task. VEH = cracker vehicle; MPH = optimal dose of methylphenidate (1.0–3.0 mg/kg); SCH = SCH23390 (0.01 or 0.1 mg/kg); ** significantly different from VEH p = 0.0002; † significantly different from MPH, p = 0.008.