Effects of Substance P in the Amygdala, Ventromedial Hypothalamus, and Periaqueductal Gray on Fear-Potentiated Startle

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.

Tracking the fear memory engram: discrete populations of neurons within amygdala, hypothalamus, and lateral septum are specifically activated by auditory fear conditioning

“…Experiments using antagonists to the neuropeptide Substance P injected into each of these three areas result in inhibition of fear-potentiated startle (Zhao et al 2009). Based on this and other data it was proposed that a critical pathway for conditioned fear runs from MeA to VMH, and is regulated by Substance P. This is consistent with our findings and supports the idea that the fear-learning circuit includes a pathway from MeA to VMH.…”

Differential Role of Muscarinic Transmission within the Entorhinal Cortex and Basolateral Amygdala in the Processing of Irrelevant Stimuli

“…Importantly, these doses were lower than the doses shown before to impair classical conditioning when infused to BLA (See et al, 2003), because impairment of conditioning per se (impaired conditioning in the NPE groups) masks the effects of experimental manipulations on LI. Infusion volume was based on a routinely used volume in similar behavioral studies ( (Barros et al, 2001;Lewis and Gould, 2007a, b;Roesler et al, 2002;Seillier et al, 2007) for EC; (Barros et al, 2001;Chhatwal et al, 2009;Milton et al, 2008;See et al, 2001See et al, , 2003Zhao et al, 2009) for BLA). Infusions were given in a different room from the behavioral testing area.…”

Effects of angiotensin (5-8) microinfusions into the ventrolateral periaqueductal gray on defensive behaviors in rats

“…However, there are evidence showing that the RAS plays a modulatory role for stress-induced hypothalamic pituitary-adrenocortical axis activation [22,75,76]. In addition to angiotensins, several other peptides exert a modulatory role on startle reactivity [77][78][79][80][81] e.g. corticotrophin-releasing factor (CRF) administration into the vlPAG induces a marked increase of startle response [82].…”