Concomitant activation of D1 dopamine and α2A adrenergic receptors for symptoms of ADHD: comparison with methylphenidate

Rationale : Methylphenidate is commonly prescribed to manage symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants it has limited 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 D _1/5 dopamine agonist 2-methyldihydrexidine; the selective α _2A adrenergic agonist guanfacine; and the cannabinoid compound cannabigerol that has α _2A agonist properties. Acute effects on temporal order memory, cognitive flexibility, and spatial working memory were evaluated using two rodent behavioral tasks. Results : Co-administration of an α _2A agonist and a D ₁ agonist produced greater cognitive improvement than methylphenidate. The performance improvement from these selective agents, however, was only observed in rats that had poor performance at baseline. Conclusions : These findings suggest that synergistic effects may emerge from the coadministration of selective agents (e.g., α _2A and D ₁ agonists) and should be considered for further study, especially as regards individuals with decrements in cognitive function.