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

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. 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 and was included given the increasing recreational cannabis use among individuals with ADHD. Acute effects on temporal order memory, cognitive flexibility, and spatial working memory were evaluated using two rodent behavioral tasks. Co-administration of an α 2A agonist and a D 1 agonist produced greater cognitive improvement than methylphenidate, but only in rats with poor baseline performance. These findings suggest that potential benefits may emerge from the coadministration of selective agents (e.g., α 2A and D 1 agonists) and should be considered for further study, especially regarding individuals with decrements in cognitive function.