Our previous investigation has demonstrated that the lack of aquaporin-4 (AQP4) expressions in mice is paralleled by sex- and region-specific abnormalities in neurotransmission. In the present study, we examined the effect of AQP4 deficiency on release of neurotransmitters in mouse striatum using in vivo microdialysis after high K(+) stimulus. The results showed that neurotransmitter releases under the basal and K(+)-stimulated conditions in the striatum of wildtype mice were similar to AQP4 knockout mice, except for taurine, when measured at 24h after microdialysis surgery. However, the basal extracellular levels of dopamine and its metabolites were significantly increased in knockout mice, followed by reduced or no response to depolarizing stimuli when measured at 7 d after surgery. In addition, it was found that there were higher responses of amino acids to high K(+) stimulus in knockout mice. This experiment provides the in vivo evidence that AQP4 participates in the regulation of neurotransmitter release induced by depolarizing stimuli.