Abstract
Bumetanide has anxiolytic effects in rat models of conditioned fear. As a loop diuretic, bumetanide blocks cation-chloride co-transport and this property may allow bumetanide to act as an anxiolytic by modulating GABAergic synaptic transmission in the CNS. Its potential for the treatment of anxiety disorders deserves further investigation. In this study, we evaluated the possible involvement of the basolateral nucleus of the amygdala in the anxiolytic effect of bumetanide. Brain slices were prepared from Wistar rats. extracellular recording, stereotaxic surgery, fear-potentiated startle response, locomotor activity monitoring and Western blotting were applied in this study. Systemic administration of bumetanide (15.2mg·kg-1 , i.v.), 30min prior to fear conditioning, significantly inhibited the acquisition of the fear-potentiated startle response. Phosphorylation of ERK in the basolateral nucleus of amygdala was reduced after bumetanide administration. In addition, suprafusion of bumetanide (5 or 10μM) attenuated long-term potentiation in the amygdala in a dose-dependent manner. Intra-amygdala infusion of bumetanide, 15min prior to fear conditioning, also blocked the acquisition of the fear-potentiated startle response. Finally, the possible off-target effect of bumetanide on conditioned fear was excluded by side-by-side control experiments. These results suggest the basolateral nucleus of amygdala plays a critical role in the anxiolytic effects of bumetanide.
Highlights
Cation–chloride co-transporters (CCCs) are transmembrane proteins that mediate transport of chloride ions across the cell membrane (Blaesse et al, 2009; Ko et al, 2014)
These results suggest the basolateral nucleus of amygdala plays a critical role in the anxiolytic effects of bumetanide
basolateral nucleus of the amygdala (BLA) is critical to anxiolytic effect of bumetanide
Summary
Cation–chloride co-transporters (CCCs) are transmembrane proteins that mediate transport of chloride ions across the cell membrane (Blaesse et al, 2009; Ko et al, 2014). There are two main types of CCCs, in which chloride is cotransported with sodium ions and/or potassium ions. Members of the sodium-coupled branch, which consists of the Na–K–Cl co-transporters, NKCC1 and NKCC2, move chloride ions into the cell and raise the intracellular concentration of chloride ([ClÀ]i) above the electrochemical equilibrium for chloride. The potassium-coupled branch, which is composed of four different K–Cl co-transporters (KCC1, KCC2, KCC3 and KCC4), primarily transport chloride ions out of the cell, reducing the [ClÀ]i below the electrochemical equilibrium of chloride (Mount et al, 1998; Kahle and Staley, 2008, 2012; Dzhala et al, 2010). Bumetanide has anxiolytic effects in rat models of conditioned fear. Brain slices were prepared from Wistar rats. extracellular recording, stereotaxic surgery, fear-potentiated startle response, locomotor activity monitoring and Western blotting were applied in this study
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