Date

6-2014

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Extinction is a complex period of learning during which a predicted relationship between stimuli (i.e. conditioned stimulus-unconditioned stimulus association) is inhibited by presentation of the predictive stimulus alone (i.e. nonreinforced conditioned stimulus), and this learning can be impaired by blockade of dopamine receptor activity. Thus, examining the relationship between dopamine and extinction may be beneficial to understanding basic features of learning and memory. Furthermore, enhancing extinction may be beneficial at a clinical level, as impaired extinction is hypothesized to contribute to a number of diseases of learning and memory, such as posttraumatic stress disorder and substance use disorders. The overarching goal of this dissertation is to examine the consequence of altering dopamine signaling during acquisition and extinction of fear and reward to specify the contribution of dopamine signaling within these particular phases of learning.

In Chapter 2, dopamine activity is manipulated through the use of ethylphenidate, a dopamine and norepinephrine transport blocker. I find that methylphenidate enhances contextual fear extinction when administered prior to or following an extinction session, and has no effect on fear acquisition. As methylphenidate may have actions through D1/5 receptors, I investigated the specific contribution of D1/5 receptors to fear extinction in Chapter 3.

Chapter 3 shows that the systemic activation of D1/5 receptors with SKF 81297 following extinction of either contextual or cued fear enhances consolidation of fear extinction. To assess the rewarding properties of SKF 81297, I utilized a conditioned place preference procedure. Pre-session, but not post-session, administration of SKF 81297 generates a conditioned place preference. I also found that post-session SKF 81297 would enhance the extinction of a cocaine conditioned place preference. These studies suggest there may be a common mechanism that underlies extinction of fear and reward within the dopamine signaling system.

Chapter 4 continues this investigation by testing whether D1 receptors are necessary for fear and reward learning in D1 receptor knockout mice. Chapter 4 shows that D1 receptor knockout enhances the expression of cued fear, but has no effect on contextual fear or cocaine conditioned place preference. Chapter 4 shows that the D1 receptor activation may not be necessary for learning fear or reward associations, although it may contribute to decreasing fear responses in certain conditions. Finally, Chapter 5 examines the neural substrates that underlie D1/5 receptor mediated extinction enhancements. I tested the effect of SKF 81297 microinjection into the infralimbic region of the prefrontal cortex, the nucleus accumbens core, dorsal hippocampus, and basolateral amygdala. I found no effect of SKF 81297 administration into these regions following extinction. Chapter 5 also examines the intracellular signaling pathways that may be involved with the observed fear extinction enhancements in Chapter 3 and finds that activation of PKA-coupled, but not PLC-coupled D1/5 receptors enhances fear extinction. Together, these experiments aim to specify the role of D1/5 receptors in fear and reward learning.

Identifier

doi:10.6083/M4513WXQ

School

School of Medicine

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