Neuropeptide Y and Cholecystokinin Modulation of the Expression and Extinction of Fear-Potentiated Startle Open Access

Gutman, Alisa (2009)

Permanent URL: https://etd.library.emory.edu/concern/etds/n296wz71s?locale=en
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


About this thesis

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Subfield / Discipline
Degree
Submission
Language
  • English
Research field
Keyword
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files