Effects of 5-HT2A Receptor Antagonism on Cocaine Self-administration, Cocaine-induced Reinstatement, and Cocaine-induced Dopamine Overflow in Rhesus Monkeys Open Access

Winschel, Jacob Edward (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/n870zr06z?locale=en
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Abstract

Growing evidence indicates that serotonin (5-HT) systems modulate the effects of stimulants by altering dopamine system function. The serotonin 2A and 2C receptor (5-HT2AR and 5-HT2CR) subtypes have been found to exhibit particularly strong, and opposing, influence on dopamine systems. For example, 5-HT2AR antagonists have been shown to inhibit stimulant-induced dopamine overflow in the nucleus accumbens (NAc) and to block both cue-induced and cocaine-primed reinstatement, although these effects have only been demonstrated in rats. These promising results suggest that 5-HT2AR antagonists may be effective therapeutics against cocaine abuse and further investigation of their therapeutic potential is warranted. Therefore, using a within-subjects design in rhesus macaques (n=3), we evaluated the effects of the selective 5-HT2AR antagonist M100,907 (M100) on intravenous cocaine self-administration and cocaine-primed reinstatement. In separate subjects, we evaluated the role of 5-HT2ARs in cocaine-induced dopamine overflow using in vivo microdialysis targeting the NAc (n=4) and the caudate nucleus (n=5). Consistent with previous studies, M100 (0.3 mg/kg, IM) did not significantly attenuate cocaine self-administration, even over a three day dosing regimen. In contrast, but also consistent with previous rat studies, M100 (0.3 mg/kg, IM) largely abolished cocaine-primed reinstatement across a range of cocaine priming doses. In accord with its lack of effect on cocaine self-administration, M100 (0.3 mg/kg, IM) did not significantly attenuate cocaine-induced dopamine overflow in the NAc. However, M100 (0.3 mg/kg, IM) significantly attenuated cocaine-induced dopamine overflow in the caudate nucleus. The concordance between the effects of M100 on cocaine-induced dopamine overflow in the caudate and cocaine-induced reinstatement supports a growing body of evidence highlighting the distinct role of the caudate in reinstatement and habit-related behaviors. Furthermore, since reinstatement procedures are the most widely accepted preclinical model of drug relapse, these findings suggest that 5-HT2AR antagonism may be a viable approach to relapse prevention in cocaine-dependent subjects. Supported by DA00517, DA 10344, and RR00165.

Table of Contents

Chapter 1: Introduction .................................................................................................................... 1 Background and Rationale ....................................................................................................... 1 Drug Abuse Prevalence and Statistics ............................................................................. 1 Prevalence of Cocaine Abuse and Dependence ............................................................... 2 Health-Related Effects of Cocaine ................................................................................... 2 Behavioral Neuropharmacology of Cocaine ............................................................................ 3 Monoamine Systems and the Abuse-Related Effects of Cocaine .................................... 3 Dopamine Systems ........................................................................................................... 6 Serotonin Systems Modulate the Effects of Cocaine ............................................................... 8 Serotonin System Neuroanatomy and Receptor Subtypes ............................................... 9 Serotonergic Modulation of Dopamine Systems ........................................................... 10 5-HT2 Receptors Modulate Effects of Stimulants ......................................................... 12 Hypotheses ............................................................................................................................. 16 Chapter 2: Materials and Methods ................................................................................................. 18 Subjects .................................................................................................................................. 18 Surgeries ................................................................................................................................ 20 Self-Administration and Reinstatement ......................................................................... 20 Microdialysis.................................................................................................................. 21 Apparatus ............................................................................................................................... 22 Self-administration and Reinstatement .......................................................................... 22 Microdialysis.................................................................................................................. 23 Procedure ............................................................................................................................... 23 Initial Self-administration Experiments ......................................................................... 23 5-HT2AR Antagonism Experiments ............................................................................... 25 Self-Administration with M100 Pretreatment ................................................................ 28 Reinstatement ................................................................................................................. 29 In vivo microdialysis ...................................................................................................... 31 High-Performance Liquid Chromatography .................................................................. 34 Data Analysis ......................................................................................................................... 34 Drugs ...................................................................................................................................... 35 Chapter 3: Results .......................................................................................................................... 36 Cocaine Self-administration ................................................................................................... 36 M100 pretreatment ......................................................................................................... 38 Reinstatement ......................................................................................................................... 40 In Vivo Microdialysis ............................................................................................................. 43 Chapter 4: Discussion .................................................................................................................... 46 Summary of Rationale ........................................................................................................... 46 Results Summary ................................................................................................................... 46 Overview ................................................................................................................................ 47 5-HT2ARs: Early Work to Mechanistic Findings ................................................................... 49 Therapeutic potential ............................................................................................................. 61 Summary ................................................................................................................................ 63 Chapter 5: References .................................................................................................................... 65

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