Objective To explore the effect of histamine on neurons in the hippocampal C1 area of SD rats and the behavior of depressive SD rats. Methods The effect of histamine on the discharge frequency of neurons in hippocampal C1 area was observed by in vitro extracellular recording of brain slices. The effect of endogenous histamine released to hippocampal neurons was observed through in vivo extracellular recording after the hypothalamus was electrically stimulated. In addition, the changes of motor activity and the ability of spatial memory of the rats with depression after microinjection of histamine into the hippocampal C1 area were observed by open?field test and Morris water maze test. Results The results of in vitro extracellular recording of brain slices showed that the hippocampal neurons were excited by histamine via H1 receptors rather than H2 receptors in a concentration dependent manner. The results of in vivo extracellular recording showed that endogenous histamine had a bidirectional effect, which means a short?term excitatory effect followed by a long term inhibitory effect on the hippocampal neurons. After injected with histamine in the hippocampal C1 area, motor activity of the depressive rats was obviously decreased during the open-field test, and the ability of spatial memory of the rats was obviously weakened in the Morris water maze test. However, motor activity and spatial memory of the depressive rats were obviously improved after injection of clobenpropit, a histamine H3 receptor antagonist. onclusions At the cellular and overall levels, histamine has a bidirectional effect on the neurons in the hippocampal C1 area, that is an effect of excitation followed by an effect of inhibition, resulting in an inhibitory effect comprehensively. Histamine can impair the motor activity and spatial memory of depressive rats, which can be obviously improved by clobenpropit, a blocker of histamine H3 receptor.