# Concomitant activation of D1 dopamine and α2A adrenergic receptors improves cognition compared with methylphenidate

## TL;DR

Combining D1 dopamine and α2A adrenergic receptor activators improved cognition more than methylphenidate in rats with poor baseline performance.

## Contribution

Demonstrates that selective receptor activation may outperform non-selective stimulants in specific cognitive contexts.

## Key findings

- Co-administration of α2A and D1 agonists improved cognition more than methylphenidate.
- Improved performance was only observed in rats with poor baseline cognitive function.
- Suggests synergistic effects from selective receptor targeting warrant further study.

## Abstract

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.

To test this hypothesis, we compared methylphenidate with three compounds: the selective D1/5 dopamine agonist 2-methyldihydrexidine; the selective α2A adrenergic agonist guanfacine; and the cannabinoid compound cannabigerol that has α2A agonist properties. Acute effects on temporal order memory, cognitive flexibility, and spatial working memory were evaluated using two rodent behavioral tasks.

Co-administration of an α2A agonist and a D1 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.

These findings suggest that synergistic effects may emerge from the coadministration of selective agents (e.g., α2A and D1 agonists) and should be considered for further study, especially as regards individuals with decrements in cognitive function.