Abstract
Abstract
Despite substantial efforts, there are currently no
pharmacotherapeutics available for the
treatment of cocaine abuse. Accumulating evidence indicates that
indirect serotonin receptor agonists attenuate the behavioral and
neurochemical effects of cocaine in animals and, accordingly,
attenuate the subjective effects of cocaine in humans, but the
specific receptor subtypes mediating these effects remain unknown.
Recent studies have demonstrated that compounds exhibiting
selectivity for both the serotonin 5-HT2A receptor (5-HT2AR) and
5-HT2C
receptor (5-HT2CR) differentially modulate the behavioral and
neurochemical effects of cocaine
in rodents, but such compounds have yet to be systematically
evaluated in nonhuman primates.
The goals of the present experiments were therefore to determine
the impact of pretreatment
with the selective 5-HT2AR antagonist M100907, the preferential and
selective 5-HT2CR agonists
mCPP and Ro 60-0175, and the selective 5-HT2CR antagonist SB
242084, upon the behavioral-
stimulant, reinforcing, reinstatement, and neurochemical effects of
cocaine in squirrel monkeys.
The results indicated that 5-HT2CR agonism attenuated, whereas
5-HT2CR antagonism enhanced,
the behavioral-stimulant and reinstatement effects of cocaine in a
dose-dependent manner.
Pretreatment with Ro 60-0175 also dose-dependently attenuated the
direct reinforcing effects
of cocaine. In contrast, administration of SB 242084 alone produced
modest behavioral-
stimulant effects and this compound also exhibited reinforcing
effectiveness when substituted
for cocaine availability in a self-administration procedure. The
impact of pretreatment with Ro
60-0175 and SB 242084 upon the behavioral effects of cocaine were
correlated with a selective
reduction or enhancement, respectively, of cocaine-induced dopamine
increases within the
mesolimbic dopamine system. Finally, pretreatment with M100907 did
not alter any behavioral
effects of cocaine. These results suggest that 5-HT2CR agonists may
represent a novel class of
pharmacotherapeutics for the treatment of cocaine abuse as they
functionally antagonized the
behavioral and neurochemical effects of cocaine in nonhuman
primates. Furthermore, the
selective 5-HT2CR antagonist SB 242084 exhibited a behavioral
profile similar to other
psychostimulants and may warrant consideration as a candidate
substitute agonist therapy for
the treatment of cocaine abuse, although the demonstration of its
reinforcing effectiveness may
be an indication of abuse liability.
Table of Contents
Table of Contents
I.
Introduction______________________________________________________________1
A. Cocaine: History and
Pharmacology_____________________________________1
1. Prevalence of Misuse
_________________________________________1
2. Pharmacological Mechanism of Action
___________________________2
B. Neuroanatomical Substrates of Cocaine Behavioral
Pharmacology ____________2
1. Overview of Brain Dopamine
Systems_____________________________2
2. The Mesocorticolimbic and Nigrostriatal DA Systems: Roles
in Cocaine-Reinforced
Behavior______________________________________________________3
a. Mesocorticolimbic System
______________________________3
b. Nigrostriatal System
___________________________________4
C. Serotonergic Modulation of Cocaine
Effects______________________________6
D. Serotonin 5-HT2 Receptor-Mediated Modulation of
Cocaine Effects___________8
1. Overview of 5-HT2 Subtype Receptors
____________________________8
2. 5-HT2C Receptor
______________________________________________10
a.
Distribution___________________________________________10
b. 5-HT2CR-Mediated Modulation of Cocaine
Effects_____________14
3. 5-HT2A Receptor
______________________________________________16
a.
Distribution___________________________________________16
b. 5-HT2AR-Mediated Modulation of Cocaine
Effects_____________17
E. Advantages of Nonhuman Primate Models of Pharmacological
Effects _________20
F. Summary and Experimental Rationales
__________________________________23
II. 5-HT2A/2C Receptors: Modulation of the
Behavioral-Stimulant Effects of Cocaine _______24
A.
Introduction________________________________________________________24
B. Methods
__________________________________________________________26
1.
Subjects_____________________________________________________26
2. Apparatus
___________________________________________________27
3. Fixed-Interval Schedule of Stimulus Termination
____________________27
4.
Drugs_______________________________________________________28
5. Data
Analysis_________________________________________________29
C. Results
____________________________________________________________29
1. 5-HT2CR Agonists: mCPP and Ro
60-0175___________________________29
2. 5-HT2CR Antagonist: SB 242084
__________________________________36
3. 5-HT2AR Antagonist:
M100907___________________________________39
D. Discussion
_________________________________________________________41
III. 5-HT2A/2C Receptors: Modulation of Cocaine
Reinforcement and Reinstatement________48
A.
Introduction________________________________________________________48
B.
Methods___________________________________________________________52
1.
Subjects_____________________________________________________52
2. Apparatus
___________________________________________________53
3. Surgeries
____________________________________________________53
4. Cocaine Self-Administration, Reinstatement, and
Substitution__________54
a. Second-Order Schedule of Cocaine
Self-Administration_________54
b. Cocaine-Induced Reinstatement
___________________________56
c. SB 242084 Substitution
__________________________________57
5. Second-Order Schedule of Stimulus
Termination_____________________58
6. Drugs
_______________________________________________________59
7. Data Analysis
_________________________________________________60
C.
Results_____________________________________________________________60
1. Cocaine-Induced
Reinstatement__________________________________60
a. 5-HT2CR Agonists: mCPP and Ro
60-0175_____________________60
b. 5-HT2CR Antagonist: SB 242084
____________________________67
c. 5-HT2AR Antagonist: M100907
_____________________________69
2. Cocaine
Self-Administration_____________________________________71
3. SB 242084
Substitution_________________________________________73
4. Stimulus Termination
__________________________________________76
D.
Discussion__________________________________________________________79
IV. 5-HT2C Receptors: Modulation of Cocaine
Neurochemical Effects in Caudate Nucleus and
Nucleus
Accumbens____________________________________________________89
A.
Introduction________________________________________________________89
B.
Methods___________________________________________________________94
1.
Subjects_____________________________________________________94
2. Apparatus
___________________________________________________95
3. Surgeries
____________________________________________________95
4.
In Vivo Microdialysis
___________________________________________96
5. Drugs
_______________________________________________________98
6. Data
Analysis_________________________________________________98
C. Results
____________________________________________________________99
1. 5-HT2CR Agonist Ro
60-0175_____________________________________99
a. Caudate Nucleus
_______________________________________99
b. Nucleus
Accumbens_____________________________________99
2. 5-HT2CR Antagonist SB
242084___________________________________101
a. Caudate
Nucleus_______________________________________101
b. Nucleus Accumbens
____________________________________103
D.
Discussion_________________________________________________________103
V. General Discussion
________________________________________________________112
VI.
References______________________________________________________________127
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