The Role of Neuropeptide Y in the Expression and Extinction of Fear-Potentiated Startle

Abstract

Neuropeptides are a promising target for novel treatments for anxiety and other psychiatric disorders and neuropeptide Y (NPY) has emerged as a key component of anxiolytic circuits in the brain. For this reason, we have evaluated the role of NPY in the expression and extinction of conditioned fear. We found that intracerebroventricular administration of NPY inhibits both baseline acoustic startle and the expression of fear-potentiated startle. Infusion of NPY (10 pmol/side) into the basolateral, but not the medial, nucleus of the amygdala reproduced the intracerebroventricular effect. Central administration of NPY (10 g) also enhanced within-session extinction of fearpotentiated startle. This finding, coupled with the growing body of literature correlating NPY with resilience in humans, led us to the hypothesis that NPY may enhance the extinction of conditioned fear. When NPY (10 g) is administered intracerebroventricularly before extinction training, extinction retention for both the contextual and cued components of conditioned fear is enhanced when tested 48 h later off drug. Additionally, we found that intra-basolateral amygdala administration of the NPY Y 1 receptor antagonist BIBO 3304 (200 pmol/side) before extinction training led to a profound deficit in extinction retention. This is the first evidence that NPY facilitates and an NPY antagonist blocks the extinction of conditioned fear. We believe that the role of NPY in the extinction of conditioned fear may, at least in part, explain the mechanism underlying the association between NPY and psychobiological resilience in humans.

Neuroprotective Effect of Neuropeptide Y against Beta-Amyloid 25–35 Toxicity in SH-SY5Y Neuroblastoma Cells Is Associated with Increased Neurotrophin Production

“…Among them, neuropeptide Y (NPY) is a small peptide widely distributed throughout the brain, where it serves as a neurotransmitter and/or a modulator of several neuroendocrine functions, including cardiovascular physiology and feeding behavior [3] . Moreover, in animal models, NPY produces behavioral effects that are similar to those induced by anxiolytics [4] , antiepileptics [5] and antidepressants [6] , suggesting that its role in the CNS neurons is multifunctional.…”

Neuropeptide Y and posttraumatic stress disorder

“…A robust reduction of contextual and cued freezing as well as fear-potentiated startle is observed following central administration of NPY. [81][82][83] The extinction of fear-potentiated startle is Y1 receptor mediated as Y1 antagonists reverse these effects. Significant attenuation of fear by NPY was also observed in a fear incubation paradigm of relevance to delayed-onset PTSD.…”

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

“…Epac is thought to be a key mediator in the effects of PACAP (Ster et al, 2009), a peptide that has been recently implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and fear memory formation (Ressler et al, 2011). Thus, NPY may modulate a variety of behaviors, including conditioned fear (Gutman et al, 2008) and human stress reactivity (Mickey et al, 2011;Witt et al, 2011) via Epac pathways and serve as a critical element in the pathophysiology of depression, PTSD, and other neuropsychiatric disorders. Indeed, several studies implicate changes in NPY levels in depression (Domschke et al, 2010;Nikisch and Mathe, 2008), anxiety disorders (Amstadter et al, 2010;Wu et al, 2011), and PTSD (Rasmusson et al, 2010;Sah et al, 2009).…”