The consequences of neurotensin deficiency on the behavioral effects of dopamine agonists and on striatal dopaminergic tone Open Access

Abstract

Numerous lines of evidence have implicated the neuropeptide neurotensin (NT) in the pathophysiology of schizophrenia. Some schizophrenic patients show decreased cerebrospinal fluid concentrations of NT, a deficit which is normalized with antipsychotic drug treatment. In rats, enhancing NT neurotransmission produces antipsychotic-like effects on behavior and mesocorticolimbic dopamine system activity, leading to the hypothesis that NT may function as an endogenous antipsychotic drug. Utilizing mice lacking the NT gene (NT-/-), this dissertation sought to examine the consequences of NT deficiency on dopaminergic function and tone. Specifically, these studies examined 1) the behavioral effects of dopamine agonists on locomotion and sensorimotor gating and 2) dopamine concentrations and dopamine receptor and transporter expression and binding in terminal regions in adult NT-/- mice compared to wildtype (NT+/+) mice. Compared to male NT+/+ mice, male NT-/- mice showed a dose-dependent attenuation of acute hyperlocomotor response and decreased sensitization to the indirect dopamine agonist amphetamine. The disruptive effects of a selective dopamine D1-type receptor agonist on locomotor activity, startle amplitude, and prepulse inhibition were dose-dependently decreased in male NT-/- mice. Male NT-/- mice also showed altered behavioral responses to a selective dopamine D2-type receptor agonist, indicating altered D1-type and D2-type receptor function in the absence of NT. Male NT-/- mice had no changes in striatal and cortical dopamine or dopamine metabolite concentrations, but showed significantly increased dorsal striatal D2 receptor mRNA and increased D2-like binding densities in the caudate putamen and nucleus accumbens, a result that is consistent with observed increases in D2 levels in schizophrenics. Female NT-/- mice did not show altered locomotor responses to acute or repeated amphetamine administration, and did not show increased striatal D2-like densities compared to female NT+/+ mice. However, female NT-/- mice showed decreased D1-like densities in the nucleus accumbens, an alteration not observed in male NT-/- mice. In sum, NT deficiency alters striatal dopamine receptor function, expression, and binding, supporting an important, sex-specific role for NT in dopamine system development and function. These studies suggest an NT deficiency may contribute to the etiology of schizophrenia.

Table of Contents

TABLE OF CONTENTS
Chapter 1: Introduction...1

1.1 Neurotensin Background...2
1.2 Dopamine Background...4
1.3 Schizophrenia, DA, AND NT...6
1.4 Anatomy of NT within the DA Systems...10
1.5 Effects of NT System Manipulation on the DA Systems...12
1.6 Effects of DA System Manipulation on the NT System...20
1.7 The Role of NT in the Locomotor Response to Pharmacological Activation of the DA Systems...24
1.8 The Role of NT in the Disruption of Sensorimotor Gating...30
1.9 Dissertation Rationale and Goals...35
Figures...37

Chapter 2: The Consequences of Neurotensin Deficiency on the Behavioral Effects of Dopamine Agonists on Locomotion and Sensorimotor Gating...43

2.1 Abstract...44
2.2 Introduction...45
2.3 Methods...48
2.4 Results...53
2.5 Discussion...59
Figures...68

Chapter 3: The Consequences of Neurotensin Deficiency on Dopaminergic Tone...76

3.1 Abstract...77
3.2 Introduction...78
3.3 Methods...80
3.4 Results...85
3.5 Discussion...87
Figures...95

Chapter 4: The Consequences of Neurotensin Deficiency in Female Mice...100

4.1 Abstract...101
4.2 Introduction...102
4.3 Methods...104
4.4 Results...107
4.5 Discussion...109
Figures...116

Chapter 5: General Discussion...120

5.1 The Role of NT in Neural Development...121
5.2 NT Knockout, DA receptor Alterations, and Behavioral Changes...125
5.3 NT Deficient Mice as an Animal Model of Schizophrenia?...127

References...132

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Keyword	neurotensin locomotor behavior schizophrenia sensorimotor gating sex differences dopamine
Committee Chair / Thesis Advisor	Nemeroff, Charles B, Emory University Kinkead, Becky, Emory University
Committee Members	Rainnie, Donald, Emory University Weinshenker, David, Emory University Young, Larry J, Emory University Pearce, Brad, Emory University

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