Neuroadaptive Changes in the Serotonin System Associated with Chronic SSRI Treatment in the Context of Cocaine Use Open Access

Sawyer, Eileen K (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/7h149q80r?locale=en
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Abstract


Abstract
Neuroadaptive Changes in the Serotonin System Associated with Chronic SSRI
Treatment in the Context of Cocaine Use
Rationale: Acute administration of selective serotonin reuptake inhibitors (SSRIs) has
been shown to attenuate the behavioral effects of cocaine in pre-clinical studies but
SSRIs have not proven successful in human clinical trials, which may be due to
differences in acute versus chronic dosing regimens. Since potential pharmacotherapies
for cocaine abuse need to be administered chronically, and the mechanism for SSRIs'
therapeutic effects is believed to be neurobiological changes that emerge during chronic,
but not acute, administration, we first designed and then examined the effects of a
clinically-relevant dosing regimen with fluoxetine on cocaine-related behavior and
neurochemistry and potential underlying mechanisms in the serotonin system.
Methods: We designed a dosing regimen with fluoxetine in rhesus macaques that
approximates human conditions over 4-6 weeks. As there is no clear serum
concentration-therapeutic effect relationship for depressive symptoms and the mechanism
for SSRIs' neurobiological changes are not well-understood, we matched the
pharmacokinetic measures as closely as possible to those reported in human clinical
studies. We then evaluated the effects of this chronic treatment (10 mg/kg/day, oral) in a
repeated measures design on cocaine self-administration, reinstatement, and dopamine
overflow in rhesus macaques trained to self-administer cocaine. In order to determine
potential neurobiological mechanisms, we examined serotonin transporter and 2A
receptor binding using positron emission tomography and serotonin overflow using in
vivo
microdialysis. Prolactin challenges served as a measure of integrated serotonin
function.
Results: Rates of ongoing cocaine self-administration behavior were not affected while
reinstatement to cocaine prime was attenuated during treatment and after washout. The
dopamine response to cocaine was also attenuated during treatment and after a 6-week
washout period. These effects were associated with a persistent increase in 5HT2A
binding potential and decreased prolactin response, despite no changes in serotonin
overflow or the transporter.
Conclusions: Together, the results suggest that chronic fluoxetine treatment is associated
with a desensitization of the 5HT2A receptor which may lead to a decrease in cocaine-
elicited dopamine overflow and thus cocaine-primed reinstatement. These results suggest
that while fluoxetine may not be an effective intervention for ongoing cocaine abuse, it
may be useful as a treatment to prevent relapse.

Table of Contents



TABLE OF CONTENTS

1. General Introduction ……………………………………………………….…….…... 1

1.1 Cocaine .………………………………………………………..…………..... 1

1.2 Serotonin and dopamine ………………………………………………..….... 3


1.2.1 SERT and SSRIs ……………………………………….…….……. 4


1.2.2 Serotonin 2A receptors ……………………………….……….…... 7

1.3 Aims and choice of model ……………………………………..…………... 11


1.3.1 Fluoxetine …………………………………………..………….… 12


1.3.2 Self-administration and reinstatement ……………..………….…. 13


1.3.3 Nonhuman primates ..………………………………………….…. 16

1.4 Summary ……………..………………………………………………….…. 17
2. Methods Development .....…...….…………………………………………………… 19

2.1 Introduction ..……………………………………………………………….. 19

2.2 Methods …………………………………………………………………….. 20

2.3 Results ……………………………………………………………………… 23

2.4 Discussion ………………………………………………………………….. 35


2.4.1 Acute pharmacokinetics ………………………………………….. 35


2.4.2 Comparative pharmacokinetics …………………………………... 35


2.4.3 Development of dosing regimen and block design ………………. 37


2.4.4 Conclusions ………………………………………………………. 39
3. Cocaine-Related Behavior and Neurochemistry …………………………………….. 40

3.1 Introduction ………………………………………………………………… 40




3.2 Methods …………………………………………………………………….. 41

3.3 Results ……………………………………………………………………… 49

3.4 Discussion ………………………………………………………………….. 57


3.4.1 Cocaine-related behavior and neurochemistry …………………… 57
3.4.2
Methodological
considerations ………………………………...… 59


3.4.3 Clinical implications …………………………………………...… 62
4. Serotonergic Neurobiology and Neurochemistry …………………………………… 63

4.1 Introduction ………………………………………………………………… 63

4.2 Methods …………………………………………………………………….. 67

4.3 Results ……………………………………………………………………… 72

4.4 Discussion ………………………………………………………………….. 90
4.4.1
SERT
regulation
and
presynaptic effects ………………………… 90


4.4.2 5HT2A regulation and post-synaptic effects …………………..… 92
4.4.3
Methodological
considerations ………………………………...… 98


4.4.4 Clinical implications ……………………………………………... 99
5. General Discussion ………………………………………………………………… 101

5.1 Importance of the model ………………………………………………..… 102

5.2 Serotonin transporter changes and cocaine ……………………………….. 103

5.3 Serotonin 2A receptors …………………………………………………… 104


5.3.1 Serotonin 2A receptors and cocaine ……………………………. 104

5.3.2 Serotonin 2A receptors and dopamine regulation .……………… 107


5.4.3 Serotonin 2A receptors and impulsivity in drug abuse …………. 108

5.4 Clinical implications .................................................................................... 111

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