TY - JOUR

T1 - Bumetanide blocks the acquisition of conditioned fear in adult rats

AU - Ko, Meng Chang

AU - Lee, Ming Chung

AU - Tang, Tso Hao

AU - Amstislavskaya, Tamara G.

AU - Tikhonova, Maria A.

AU - Yang, Yi Ling

AU - Lu, Kwok Tung

N1 - © 2017 The British Pharmacological Society.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Background and Purpose: 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. Experimental Approach: 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. Key Results: Systemic administration of bumetanide (15.2 mg·kg-1, i.v.), 30 min 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 10 μM) attenuated long-term potentiation in the amygdala in a dose-dependent manner. Intra-amygdala infusion of bumetanide, 15 min 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. Conclusions and Implications: These results suggest the basolateral nucleus of amygdala plays a critical role in the anxiolytic effects of bumetanide.

AB - Background and Purpose: 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. Experimental Approach: 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. Key Results: Systemic administration of bumetanide (15.2 mg·kg-1, i.v.), 30 min 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 10 μM) attenuated long-term potentiation in the amygdala in a dose-dependent manner. Intra-amygdala infusion of bumetanide, 15 min 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. Conclusions and Implications: These results suggest the basolateral nucleus of amygdala plays a critical role in the anxiolytic effects of bumetanide.

KW - BASOLATERAL AMYGDALA

KW - CATION-CHLORIDE COTRANSPORTERS

KW - CONCISE GUIDE

KW - D-CYCLOSERINE

KW - EAA RELEASE

KW - INDUCED BRAIN EDEMA

KW - K-CL COTRANSPORTER

KW - KINASE

KW - NUCLEUS

KW - POTENTIATED STARTLE

UR - http://www.scopus.com/inward/record.url?scp=85045283870&partnerID=8YFLogxK

U2 - 10.1111/bph.14125

DO - 10.1111/bph.14125

M3 - Article

C2 - 29235092

AN - SCOPUS:85045283870

VL - 175

SP - 1580

EP - 1589

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 10

ER -