Concomitant activation of D1 dopamine and α2A adrenergic receptors improves cognition better than methylphenidate in two rodent behavioral tests

Abstract Rationale: Methylphenidate is commonly prescribed to manage symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants it has variable effectiveness. Methylphenidate works by increasing the synaptic availability of dopamine and norepinephrine, resulting in stimulation of dopaminergic and adrenergic receptors. One hypothesis is that selective receptor targeting may be more effective clinically and have fewer side effects than non-selective stimulants. Objectives and methods: To test this hypothesis, we compared methylphenidate with three compounds: the selective D1/5 dopamine agonist 2-methyldihydrexidine; the