Abstract
The neural pathways through which substance P (SP) influences fear and anxiety are poorly understood. However, the amygdala, a brain area repeatedly implicated in fear and anxiety processes, is known to contain large numbers of SP-containing neurons and SP receptors. Several studies have implicated SP neurotransmission within the amygdala in anxiety processes. In the present study, we evaluated the effects of site-specific infusions of an SP receptor antagonist, GR 82334, on conditioned fear responses using the fear-potentiated startle paradigm. GR 82334 infusion into the basolateral (BLA) or the medial (MeA) nuclei of the amygdala, but not into the central nucleus of the amygdala (CeA), dose dependently reduced fear-potentiated startle. Similar effects were obtained with GR 82334 infusion into the ventromedial nucleus of the hypothalamus (VMH), to which the MeA projects, and into the rostral dorsolateral periaqueductal gray (PAG), to which the VMH projects, but not into the deep layers of the superior colliculus/deep mesencephalic nucleus (dSC/DpMe), an output of the CeA previously shown to be important for fear-potentiated startle. Consistent with previous findings, infusion of the AMPA receptor antagonist, NBQX, into the dSC/DpMe, but not into the PAG, did disrupt fear-potentiated startle. These findings suggest that multiple outputs from the amygdala play a critical role in fear-potentiated startle and that SP plays a critical, probably modulatory role, in the MeA to VMH to PAG to the startle pathway based on these and data from others.
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Acknowledgements
This research was supported by National Institute of Mental Health Grants MH47840, MH57250, and MH59906; the Science and Technology Center (the Center for Behavioral Neuroscience of the National Science Foundation under Agreement no. IBN-9876754); and the Yerkes Base Grant.
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DISCLOSURE/CONFLICT OF INTEREST
The authors have no conflict of interest to report related to the finding in this study. However, Dr Michael Davis does have a project on a grant from the NIMH (U19 MH06905602) to test compounds supplied by GlaxoSmithKline, one of which is an NK1 antagonist.
Michael Davis
SAB Helicon Corp.—now terminated
Consultant, Repligen Corp.—2002–2005
Consultant, Amgen Corp.—2 January 2004
Consultant, AstraZeneca—6 June 2006
Consultant, Tikvah Therapeutics Inc.—2007–present
Research support—Repligen Corp.—2002–2005
Research support—AstraZeneca
Unrestricted gift—AstraZeneca
Dr Davis has a patent pending for the use of cognitive enhancers, in particular, D-cycloserine, to be used as an adjunct to psychotherapy. Tikvah Therapeutics Inc. has licensed this technology to commercialize the use of D-cycloserine as an adjunct to psychotherapy. He is a partner in a company called Therapade and has received a signing fee. He will then receive certain milestone payments over the next several years. Once the indication is approved by the FDA, he is entitled to royalties.
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Zhao, Z., Yang, Y., Walker, D. et al. Effects of Substance P in the Amygdala, Ventromedial Hypothalamus, and Periaqueductal Gray on Fear-Potentiated Startle. Neuropsychopharmacol 34, 331–340 (2009). https://doi.org/10.1038/npp.2008.55
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DOI: https://doi.org/10.1038/npp.2008.55
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