Neuropeptide Y and Cholecystokinin Modulation of the Expressionand Extinction of Fear-Potentiated Startle Public
Gutman, Alisa (2009)
Published
Abstract
Abstract Neuropeptide Y and Cholecystokinin Modulation of the Expression and Extinction of Fear-Potentiated Startle By Alisa R. Gutman Neuropeptides are a promising target for novel treatments for anxiety and other psychiatric disorders. Two major candidates are neuropeptide Y (NPY) and cholecystokinin (CCK) and, for this reason, we focus on these peptides and their role in the expression and extinction of conditioned fear. We found that intracerebroventricular (i.c.v.) 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 i.c.v. effect. Central administration of NPY (10 g) also enhanced within-session extinction of fear-potentiated 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 i.c.v. prior to extinction training, extinction retention for both the contextual and cued components of conditioned fear is enhanced when tested 48 hours later off drug. Additionally, we found that intra-basolateral amygdala administration of the NPY Y1 receptor antagonist BIBO 3304 (200 pmol/side) prior to extinction training led to a profound deficit in extinction retention. 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. Conversely, central infusion of pentagastrin, a CCK2 receptor agonist, prior to extinction training yields impaired extinction retention. Anatomical studies have shown overlap between the CCK and endocannabinoid systems, and genetic and pharmacological studies indicate that CB1 receptors are involved in extinction. Based on this, we performed a series of experiments assessing interactions between the
endocannabinoid and CCK systems. These studies indicate that both systemic (3 mg/kg) and intra-basolateral amygdala (1 g) administration of the CCK2 antagonist CR2945 prior to extinction training reverses the blockade of extinction that we find following i.p. injection of the CB1 receptor antagonist SR141716A (5 mg/kg). Overall, these results suggest that enhancement of the NPY system and blockade of the CCK system may be beneficial for individuals with post-traumatic stress disorder and other anxiety disorders.
Table of Contents
Table of Contents
Page Chapter 1, Introduction Fear Conditioning 2 Fear-Potentiated Startle 3 Amygdala Anatomy 5 Fear Anatomy and Pharmacology 6 Neuropeptides 8 References 10 Chapter 2, The Role of Neuropeptide Y in the Expression of Fear-Potentiated Startle Introduction 16 Materials and Methods 26 Results 32 Discussion 34 References 38 Chapter 3, The Role of NPY in the Extinction of Fear-Potentiated Startle Introduction 58 Materials and Methods 63 Results 67 Discussion 69 References 74 Chapter 4, The Role of Cholecystokinin in the Extinction of Fear-Potentiated Startle Introduction 89 Materials and Methods 95 Results 99 Discussion 102 References 106 Chapter 5, Conclusion Summary of Findings 122 Gut Peptides and Anxiety 123 Future Directions 125 Clinical Implications 128 References 130
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