An examination of the role of serotonin 2C (5-HT2C) receptors in psychostimulant self-administration in rhesus macaques. Pubblico

Abstract

Psychostimulants like cocaine (COC) and amphetamines are some of the most commonly abused drugs, however no effective treatments have been developed for psychostimulant abuse. Additionally, some populations are at increased risk for drug abuse due to early life stress (ELS) experiences and other factors such as gender or drug initiation during adolescence. The 5-HT2C receptor has been of interest as a target for the treatment of psychostimulant addiction due to its modulation of dopaminergic activity in the nucleus accumbens. The aim of the present study was to investigate the effects of a selective 5-HT2C receptor agonist WAY 163909 (WAY) on COC self-administration (SA) in adolescent rhesus monkeys that were hypothesized to be at greater risk for COC abuse due to ELS. Subjects were 8 adolescent rhesus monkeys. Six subjects experienced ELS in the form of maternal maltreatment as infants (MALT) and 2 did not (Control). Mother-infant pairs were studied from birth through 3 months postpartum to examine the maternal care received, and infant maltreatment was operationally defined as co-occurrence of physical abuse and infant rejection. In adolescence (at approximately 4-5 years of age), subjects began COC SA studies, including acquisition of SA, peak dose (EDMax) determination, Limited Access (LA) sessions, and WAY pretreatments before COC SA to examine its effects on SA. Outcome measures were number of infusions and response rate. Rate of acquisition of cocaine SA was not significantly different between Control and MALT groups, however mean EDMax was significantly lower in MALT subjects. Baseline number of infusions, but not response rate, was significantly greater in MALT subjects. WAY pretreatments significantly decreased responding in all subjects at the highest dose, however there were no significant differences in responding after WAY between groups. This suggests that potential therapeutic treatments for psychostimulant abuse that target the 5-HT2C receptor may be effective at reducing drug intake with minimal side effects in multiple different populations. Future studies are warranted in order to make stronger conclusions regarding the relationship between ELS and serotonergic regulation of the mesolimbic system. 

Table of Contents

1. Introduction & Background................................................... 1

          a. Drug Abuse ................................................................. 1

          b. Monoamine Systems ................................................... 1

          c. Nonhuman Primate Models of Drug Abuse ................ 3

         d. Serotonin 2C (5-HT2C) Receptor ................................ 5

          e. Early Life Stress: Risk Factor for Drug Abuse ........... 6

          f. Nonhuman Primate Models of Early Life Stress.......... 9

2. Hypothesis............................................................................ 12

3. Methods................................................................................ 13

4. Results.................................................................................. 18

5. Discussion............................................................................ 20

6. Conclusion........................................................................... 26

7. Tables & Figures.................................................................. 28

a. Table 1: Mean Number of Infusions ........................  28

b. Table 2: Mean Response Rates ................................. 29

c. Figure 1: Study Design ............................................. 30

d. Figure 2: Acquisition ................................................ 31

e. Figure 3: EDMax ......................................................... 32

f. Figure 4: Individual Dose-Response Curves.............. 33

g. Figure 5: Baseline Infusions ..................................... 34

h. Figure 6: Baseline Response Rates ........................... 35

i. Figure 7: Effect of WAY on Number of Infusions ..... 36

 

          j. Figure 8: Effect of WAY on Response Rates ............. 37

8. References........................................................................... 38 

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Parola chiave	cocaine early life stress pharmacology 5-HT2C receptor addiction
Committee Chair / Thesis Advisor	Sanchez, Mar, Emory University
Committee Members	Gourley, Shannon, Emory University Wakeford, Alison, Emory University Roesch, Leah, Emory University

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