D1 agonist dihydrexidine releases acetylcholine and improves cognitive performance in rats.

Dihydrexidine is a selective, full-efficacy dopamine D1 receptor agonist that has displayed therapeutic potential in Parkinson's disease by reversing motor deficits of MPTP-treated monkeys. The present study monitored the effects of dihydrexidine on acetylcholine release in rat brain by using in vivo microdialysis. Moderate doses of dihydrexidine [3 and 10 mg/kg, intraperitoneally (I.P.)] elevated extracellular concentrations of acetylcholine by 40-60% in rat striatum; higher doses did not significantly alter acetylcholine release. SCH 23390 blocked the dihydrexidine-induced increase, indicating a D1 receptor-mediated action. A more robust stimulatory effect of dihydrexidine on acetylcholine release was observed in prefrontal cortex (to 300% of basal output) than in striatum. Dihydrexidine was also evaluated in a passive avoidance procedure in rats to determine if its neurochemical effects translated into cognition-enhancing activity; in this assay, dihydrexidine (0.3 mg/kg, I.P.) significantly improved the scopolamine-induced deficits. The results of these studies suggest that the acetylcholine-releasing properties of dihydrexidine and other D1 agonists may underlie their cognition-enhancing activity and thus may have clinical value in the treatment of dementia.