Serotonin 5-HT2C Receptor-Mediated Modulation of the Behavioral and Neurochemical Effects of Cocaine in the Squirrel Monkey Open Access

Manvich, Daniel (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/qf85nb85s?locale=en
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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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