Effects of pharmacological dopamine β-hydroxylase inhibition on cocaine-induced behavior and neurochemistry Público

Cooper, Debra Andrea (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/9k41zf07g?locale=pt-BR
Published

Abstract

Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical
settings, though it has many molecular targets and the behavioral and molecular mechanisms
underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of
dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine (NE)
in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA levels
in the brain. Because we know that relapse-like behavior in animal models depends on NE
signaling, we hypothesized that DBH inhibition and the subsequent reduction in NE levels
mediates the therapeutic effects of disulfiram. Indeed, we found that disulfiram decreased brain
NE levels and blocked cocaine-primed reinstatement of drug seeking in rats (a commonly used
model of relapse), consistent with clinical results. Furthermore, nepicastat, a selective DBH
inhibitor that lacks disulfiram's target promiscuity and adverse side effects, also blocks cocaine-
primed reinstatement in rats, supporting the use of DBH inhibitors for the treatment of cocaine
dependence. We next assessed the ability of DBH inhibitors to reduce cocaine seeking in non-
human primates. Squirrel monkeys trained to self-administer cocaine under a second-order
schedule were pretreated with disulfiram or nepicastat prior to cocaine-primed reinstatement
sessions. Neither pretreatment altered cocaine-primed reinstatement. Unexpectedly, when
administered alone, nepicastat was sufficient to induce a modest reinstatement effect. To
investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH
inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo
microdialysis in squirrel monkeys. Nepicastat had no effect on basal extracellular DA levels in
the NAc, but attenuated cocaine-induced DA overflow. These results suggest that there may be
species or methodological differences between rats and non-human primates that influence the
behavioral and neurochemical discrepancies. Understanding the discrepancies between the
animal models will ultimately be instrumental in influencing the translation of these therapies to
a human population and determining under what specific circumstances DBH inhibition is a
suitable treatment for preventing relapse to cocaine abuse.

Table of Contents

TABLE OF CONTENTS

I. Introduction

A. Cocaine History ...................................................................................................1

B. Pharmacological Mechanisms..............................................................................3

C. Neuroanatomical Substrates of Cocaine-Mediated Behaviors ............................4

D. Norepinephrine and Reinforcing Behaviors .........................................................5

E. Role of Dopamine Beta-Hydroxylase in Abuse Related Behaviors .....................9

F. Advantages of Nonhuman Primate Models of Pharmacological Effects ............13

G. Summary and Experimental Rationales ............................................................16

II. Pharmacological DBH Inhibition: Effect on Cocaine Reinforcement and

Reinstatement in Rats ...............................................................................................18

A. Introduction ........................................................................................................18

B. Methods .............................................................................................................20

1. Subjects ....................................................................................................20

2. Drugs .........................................................................................................20

3. Quantification of Catecholamine Levels ....................................................22

4. Food Training ............................................................................................23

5. Surgery ......................................................................................................24

6. Cocaine Self-Administration and Reinstatement .......................................24

a. Cocaine Self-Administration .............................................................24

b. Extinction ..........................................................................................25

c. Cocaine Primed-Reinstatement.............................................................25

7. Food Self-Administration and Reinstatement............................................26

a. Food Self-Administration ..................................................................26

b. Food-Primed Reinstatement ............................................................26

8. Data Analysis ............................................................................................27

C. Results ..............................................................................................................27

1. Disulfiram Inhibits DBH and Decreases Brain NE Levels .........................27

2. Disulfiram Has No Effect on Self-Administration of Food or Cocaine .......29

3. Disulfiram Blocks Cocaine-Primed Reinstatement of Cocaine Seeking ...29

4. Nepicastat Blocks Cocaine-Primed Reinstatement of Cocaine Seeking ..32

D. Discussion .........................................................................................................39

III. Pharmacological DBH Inhibition: Effect on Cocaine Reinstatement in Squirrel Monkeys .................................................................................................................43

A. Introduction ........................................................................................................43

B. Methods .............................................................................................................46

1. Subjects ....................................................................................................46

2. Apparatus ..................................................................................................46

3. Surgeries ...................................................................................................47

4. Cocaine Self-Administration and Reinstatement .......................................48

a. Second Order Self-Administration ....................................................48

b. Cocaine-Primed Reinstatement .......................................................49

c. Yohimbine-Primed Reinstatement ....................................................50

d. Nepicastat-Primed Reinstatement ....................................................50

5. Drugs .........................................................................................................51

6. Data Analysis ............................................................................................51

C. Results ..............................................................................................................52

1. Cocaine-Primed Reinstatement ................................................................52

a. Disulfiram Pretreatment ....................................................................52

b. Nepicastat Pretreatment ...................................................................52

2. Yohimbine-Primed Reinstatement ............................................................58

3. Nepicastat Primed-Reinstatement ............................................................58

D. Discussion .........................................................................................................61

IV. Pharmacological DBH Inhibition: Effect on Striatal Neurochemistry in Squirrel Monkeys .................................................................................................................70

A. Introduction ........................................................................................................70

B. Methods .............................................................................................................73

1. Subjects ....................................................................................................73

2. Apparatus ..................................................................................................74

3. Surgeries ...................................................................................................74

4. In Vivo Microdialysis ..................................................................................75

5. Drugs ........................................................................................................77

6. Data Analysis ............................................................................................77

C. Results ..............................................................................................................78

1. In Vivo Microdialysis ..................................................................................78

a. Basal DA levels ................................................................................78

b. Cocaine Induced DA Overflow..........................................................81

D. Discussion .........................................................................................................84

V. General Discussion ....................................................................................................89

VI. References ..............................................................................................................101

LIST OF FIGURES

1. Catecholamine biosynthetic pathway .........................................................................28

2. Effect of disulfiram on catecholamine levels in the rat prefrontal cortex .....................30

3. Disulfiram does not affect maintenance of cocaine self-administration in rats ...........31

4. Disulfiram blocks cocaine-primed reinstatement in rats .............................................33

5. Effect of nepicastat on catecholamine levels in the rat prefrontal cortex ....................35

6. Nepicastat does not affect maintenance of cocaine self-administration in rats ..........36

7. Nepicastat blocks cocaine-primed reinstatement in rats ............................................37

8. Nepicastat does not affect food-primed reinstatement of food seeking in rats ...........38

9. Disulfiram does not affect cocaine-primed reinstatement in squirrel monkeys ...........53

10. Nepicastat pretreatment on cocaine-primed reinstatement in squirrel monkeys ......54

11. Nepicastat does not affect cocaine-primed reinstatement in squirrel monkeys ........56

12. Effect of nepicastat on cocaine-primed reinstatement in squirrel monkeys ..............57

13. Effect of nepicastat on yohimbine-primed reinstatement in squirrel monkeys ..........59

14. Nepicastat administered alone induces reinstatement in squirrel monkeys .............60

15. Effects of disulfiram on striatal DA release in squirrel monkeys..............................79

16. Effect of nepicastat on striatal DA release in squirrel monkeys ................................80

17. Effects of disulfiram on cocaine-induced striatal DA release squirrel monkeys .......82

18. Effects of nepicastat on cocaine-induced striatal DA release squirrel monkeys .......83

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