The D1 agonist dihydrexidine releases acetylcholine and improves cognition in rats

Neurochemical and behavioral studies have elucidated extensive interactions between dopaminergic and cholinergic systems in brain areas associated with movement and cognition. The initial goal of these studies was to evaluate the effect of the anti-Parkinson drug dihydrexidine (DHX), a dopamine D1 full-efficacy agonist, on brain acetylcholine (ACh) release using in vivo microdialysis techniques. Moderate doses of DHX (3 and 10 mg/kg) produced approximately a 50% increase in striatal ACh release that was blocked by the D1 agonist SCH23390 (0.3 mg/kg). A higher dose of DHX (17.5 mg/kg) was less effective in raising striatal ACh, possibly due to D2 receptor activation. In frontal cortex, DHX (10 mg/kg) evoked a more robust increase in ACh release (+200%) that was blocked by SCH23390 (0.3 mg/kg). Since elevations in brain ACh are associated with cognitive improvement, the effectiveness of DHX in a passive avoidance model of learning and memory was also evaluated. These studies revealed a significant improvement in performance by 0.3 mg/kg DHX in scopolamine-induced amnestic rats. These results provided support for the hypothesis that DHX improves cognitive performance as a consequence of ACh release in relevant brain regions. Further, D1 agonists may have novel therapeutic potential in the treatment of dementia.