4-Hydroxybenzyl methyl ether improves learning and memory in mice via the activation of dopamine D1 receptor signaling

The phenolic compound 4-hydroxybenzyl methyl ether (HBME) is isolated from Gastrodia elata Blume (Orchidaceae). In the present study, we investigated the effect of HBME on three stages of memory (acquisition, consolidation, and retrieval) using the step-through passive avoidance task. HBME was administered at 3 time points; 1 h before the acquisition trial, immediately after the acquisition trial, and 1 h before the retention trial, respectively. HBME (10 mg/kg, p.o.) markedly increased the step-through latency compared with the vehicle-treated control at all stages of memory. To clarify the mechanism of the memory-enhancing effect of HBME, an antagonism study and Western blot analysis were performed. The enhancing effects of HBME on each phase were reversed by the sub-effective dose of the dopamine D1 receptor antagonist SCH23390 (0.0125 mg/kg, s.c.), or the protein kinase A (PKA) antagonist H-89 (0.25 mg/kg, i.p.). In addition, the administration of HBME (10 mg/kg, p.o.) significantly increased the phosphorylation of the cortical and hippocampal PKA/cAMP response element-binding protein (CREB), and was reversed by the co-administration of SCH23390. HBME (10 mg/kg, p.o.) also ameliorated the memory impairment induced by SCH23390 or scopolamine. Taken together, these results suggest that the effect of HBME on cognitive functions may be partly involved in dopaminergic neurotransmitter signaling and that HBME could be a potential therapeutic agent for treating the cognitive dysfunction induced by dopaminergic or cholinergic neurotransmitter system deficits.