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Author Notes:

Correspondence: Donald G. Rainnie, Ph.D., Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA; Email: drainni@emory.edu; Fax: (404) 727 8070; Tel: (404) 712 9714

Acknowledgments: The authors want to thank Dr. Allan Levey for constructive comments and help in supplying the knock-out mice and Marcelia Maddox for technical assistance in EM studies.


Research Funding:

This work was supported by National Institute of Mental Health Grant MH-072908 to D. G. Rainnie; and the Yerkes National Primate Research Center Base Grant RR-00165 awarded by the Animal Resources Program of National Institutes of Health.


  • Acetylcholine
  • Eserine
  • Carbachol
  • Muscarinic receptor knockout mice
  • EPSCs

Presynaptic Muscarinic M2 Receptors Modulate Glutamatergic Transmission in the Bed Nucleus of the Stria Terminalis


Journal Title:



Volume 62, Number 4


, Pages 1671-1683

Type of Work:

Article | Post-print: After Peer Review


The anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG) serves as an important relay station in stress circuitry. Limbic inputs to the BNSTALG are primarily glutamatergic and activity-dependent changes in this input have been implicated in abnormal behaviors associated with chronic stress and addiction. Significantly, local infusion of acetylcholine (ACh) receptor agonists into the BNST trigger stress-like cardiovascular responses, however, little is known about the effects of these agents on glutamatergic transmission in the BNSTALG. Here, we show that glutamate- and ACh-containing fibers are found in close association in the BNSTALG. Moreover, in the presence of the acetylcholinesterase inhibitor, eserine, endogenous ACh release evoked a long-lasting reduction of the amplitude of stimulus-evoked EPSCs. This effect was mimicked by exogenous application of the ACh analogue, carbachol, which caused a reversible, dose-dependent, reduction of the evoked EPSC amplitude, and an increase in both the paired pulse ratio and coefficient of variation, suggesting a presynaptic site of action. Uncoupling of postsynaptic G-proteins with intracellular GDP-β-S, or application of the nicotinic receptor antagonist, tubocurarine, failed to block the carbachol effect. In contrast, the carbachol effect was blocked by prior application of atropine or M2 receptor-preferring antagonists, and was absent in M2/M4 receptor knockout mice, suggesting that presynaptic M2 receptors mediate the effect of ACh. Immuno-electron microscopy studies further revealed the presence of M2 receptors on axon terminals that formed asymmetric synapses with BNST neurons. Our findings suggest that presynaptic M2 receptors might be an important modulator of the stress circuit and hence a novel target for drug development.

Copyright information:

© 2011 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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