Distinct Effects of Nonselective Rho-Kinase Inhibitor Fasudil and Selective Rho-Kinase 2 Inhibitor KD025 on Serotonin...

Recent studies have indicated that the Rho GTPase family and Rho-kinases are associated with psychiatric diseases, such as schizophrenia. Two subtypes of Rho-kinase, Rho-kinases 1 and 2, regulate actin dynamics and mediate neurite outgrowth, spine morphology in neurons, and neurotransmitter release in vitro and ex vivo. However, the precise role of Rho-kinases in neurotransmitter release in vivo remains unclear. To clarify the role of Rho-kinases 1 and 2 in serotonin and dopamine release in the nucleus accumbens (NAc) of mice in vivo, we investigated the effect of a nonselective Rho-kinase inhibitor, fasudil, and a selective Rho-kinase 2 inhibitor, KD025, using an in vivo microdialysis technique. Fasudil perfusion (1-20 μM) into the NAc increased the basal extracellular serotonin level but did not affect dopamine levels, whereas KD025 (10-20 μM) had little effect on basal serotonin and dopamine levels. Notably, fasudil perfusion into the NAc suppressed depolarization-induced serotonin and dopamine release in a dose-dependent manner, whereas KD025 selectively suppressed depolarization-induced serotonin release. Our results suggested that Rho-kinases 1 and 2 are associated with dopamine and serotonin release, respectively, and that both may have significant but distinct roles in the regulation of serotonin and dopamine release in the NAc.