Enhancement of learning behaviour by a potent nitric oxide‐guanylate cyclase activator YC‐1

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Abstract
Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC‐1, which is a benzylindazole derivative, greatly potentiated the response of soluble guanylate cyclase to NO (up to several hundreds fold). We have previously shown that YC‐1 markedly enhances long‐term potentiation in hippocampal and amygdala slices via NO‐cGMP‐PKG‐dependent pathway. We here further investigated whether YC‐1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC‐1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC‐1 30 min after foot‐shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC‐1 inhibited the scopolamine‐induced learning deficit. The enhancement of learning behaviour by YC‐1 was antagonized by intracerebroventricular injection of NOS inhibitor L‐NAME and PKG inhibitors of KT5823 and Rp‐8‐Br‐PET‐cGMPS, indicating that NO‐cGMP‐PKG pathway is also involved in the learning enhancement action of YC‐1. YC‐1 is thus a good drug candidate for the improvement of learning and memory.