Role of Glutamate on Dopamine Neurochemistry and the Behavioral Pharmacology of Cocaine in Squirrel Monkeys Público

Abstract

Abstract
Role of Glutamate on Dopamine Neurochemistry and the Behavioral Pharmacology of
Cocaine in Squirrel Monkeys
By Rayna M. Bauzo
Basal glutamate originating primarily from the cystine-glutamate transporter provides
glutamatergic tone on extrasynaptic glutamate receptors such as the metabotropic
glutamate 2/3 receptors (mGluR2/3). Glutamate has been shown to regulate dopamine
function in the mesocorticolimbic pathway in rodents, which plays an important role in
the behavioral pharmacology of psychostimulants. Hence, glutamate systems may be
effective targets for cocaine pharmacotherapeutics. To investigate whether cystine-
glutamate transporter or mGluR2/3 modulation would alter the neurochemical and
behavioral effects of cocaine, NAC, a cystine prodrug, and LY379268, an mGluR2/3
agonist, were administered prior to cocaine during in vivo microdialysis and operant
behavioral tasks. It was hypothesized that augmenting extrasynaptic glutamate release
or mGluR2/3 activation would attenuate cocaine- or amphetamine-induced increases in
extracellular dopamine and their corresponding behavioral-stimulant, reinforcing and
reinstatement effects. NAC significantly attenuated cocaine-induced increases in
dopamine but had inconsistent effects on amphetamine-induced increases in dopamine.
However, NAC did not alter the behavioral effects of either cocaine or amphetamine.
Similarly, LY379268 significantly attenuated cocaine-induced increases in dopamine.
LY379268 also significantly attenuated cocaine-induced behavioral-stimulant effects but
drug interactions on cocaine self-administration and reinstatement were less robust and
inconsistent across pretreatment doses. Hence, drug interactions on neurochemistry
were only partially reflected in behavioral measures, likely due to the incomplete
blockade of cocaine-induced increase in extracellular dopamine by NAC and LY379268.

Table of Contents

Table of Contents Acknowledgements Dedication Table of Contents Table of Figures Table of Tables I. INTRODUCTION............................................................................................................ 1 A. Specific aims.............................................................................................................. 2 II. BACKGROUND AND SIGNIFICANCE................................................................................... 4 A. Cocaine abuse............................................................................................................ 4 B. Rationale for Targeting Dopamine:.................................................................................. 4 C. Rationale for targeting Glutamate:.................................................................................. 8 D. Cystine-glutamate transporter...................................................................................... 11 E. Metabotropic glutamate receptors................................................................................. 14 F. Pathways................................................................................................................. 17 III. MATERIALS AND METHODS......................................................................................... 20 A. GENERAL METHODS.................................................................................................... 20 1. Subjects.................................................................................................................. 20 a. Nonhuman Primates.................................................................................................... 20 b. Rodents................................................................................................................... 20 2. Drugs...................................................................................................................... 21 3. Statistical analyses................................................................................................... 23 B. METHODS USED IN MICRODIALYSIS STUDIES - NONHUMAN PRIMATE................................... 23 1. Apparatus................................................................................................................ 23 2. Guide cannula implantation.......................................................................................... 24 3. Verification of guide cannula placement......................................................................... 24 4. Experimental procedures............................................................................................. 25 C. METHODS USED IN MICRODIALYSIS STUDIES - RODENTS.................................................. 28 1. Apparatus................................................................................................................ 28 2. Guide cannula implantation.......................................................................................... 28 3. Verification of guide cannula placement......................................................................... 29 4. Experimental procedures............................................................................................. 29 D. METHODS USED IN BEHAVIORAL STUDIES...................................................................... 30 1. Apparatus............................................................................................................... 30 2. Catheter implantation................................................................................................ 30 3. Schedules of reinforcement........................................................................................ 31 a. Fixed-interval stimulus termination............................................................................... 31 b. Cocaine self-administration........................................................................................ 31 c. Reinstatement......................................................................................................... 33 E. PHARMACOLOGICAL STUDIES..................................................................................... 33 1. Microdialysis experiments - Nonhuman Primates............................................................. 33 2. Microdialysis experiments - Rodents............................................................................ 36 3. Fixed-interval stimulus termination studies.................................................................... 37 4. Drug self-administration experiments........................................................................... 39 5. Reinstatement experiments........................................................................................ 40 IV. Results - Effects of cystine-glutamate transporter modulation on the neurochemical and behavioral effects of cocaine............................ 42 A. Introduction............................................................................................................ 42 B. Results................................................................................................................... 43 1. Microdialysis............................................................................................................ 43 2. Fixed-interval stimulus termination............................................................................... 47 3. Self-administration and Reinstatement......................................................................... 48 C. Discussion.............................................................................................................. 49 D. Figures for the effects of NAC on the neurochemical and behavioral effects of cocaine......... 53 V. EFFECTS OF mGluR2/3 MODULATION ON THE NEUROCHEMICAL AND BEHAVIORAL EFFECTS OF COCAINE................................................ 71 A. Introduction............................................................................................................ 71 B. Results................................................................................................................... 73 1. Microdialysis............................................................................................................ 73 2. Fixed-interval stimulus termination............................................................................... 74 3. Self-administration.................................................................................................... 75 4. Reinstatement.......................................................................................................... 75 C. Discussion............................................................................................................... 76 D. Figures for the effects of LY379268 on the neurochemical and behavioral effects of cocaine... 80 VI. Discussion............................................................................................................... 90 A. Limitations............................................................................................................... 99 B. Future Directions...................................................................................................... 101 C. Conclusion...............................................................................................................102 VII. Bibliography........................................................................................................... 104

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	nonhuman primate cocaine stimulant metabotropic glutamate in vivo microdialysis glutamate amphetamine dopamine self-administration
Committee Chair / Thesis Advisor	Howell, Leonard, Emory University
Committee Members	Wilson, Mark, Emory University Bergman, Jack , Harvard Medical School Kimmel, Heather, Emory University Smith, Yoland, Emory University

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