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Author Notes:

Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA, Tel: +1 404 727 7786; Fax: +1 404 727 1266; E-mail: lhowell@emory.edu

We acknowledge Lisa Neidert, Juliet Brown, and Paul Chen for expert technical assistance. We also thank Dr James Ritchie and Bailey Glover for providing the MS/MS analyses of fluoxetine concentrations and the Yerkes BioMarkers Core for the prolactin analyses. A portion of this work was submitted in partial fulfillment of the dissertation requirements of Emory University.



  • fluoxetine
  • cocaine
  • self-administration
  • reinstatement
  • nonhuman primate
  • 5HT2A
  • clinical or preclinical
  • serotonin
  • addiction & substance abuse
  • neuropharmacology
  • fluoxetine
  • cocaine
  • self-administration
  • reinstatement
  • nonhuman primate

Neurobiological Changes Mediating the Effects of Chronic Fluoxetine on Cocaine Use


Journal Title:



Volume 37, Number 8


, Pages 1816-1824

Type of Work:

Article | Post-print: After Peer Review


Acute SSRI (selective serotonin reuptake inhibitor) treatment has been shown to attenuate the abuse-related effects of cocaine; however, SSRIs have had limited success in clinical trials for cocaine abuse, possibly due to neurobiological changes that occur during chronic administration. In order to better understand the role of serotonin (5HT) in cocaine abuse and treatment, we examined the effects of chronic treatment with the SSRI fluoxetine at clinically relevant serum concentrations on cocaine-related neurobiology and behavior. Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans. Self-administration and reinstatement were monitored throughout the treatment and washout period. In vivo microdiaylsis was used to assess changes in dopaminergic and serotonergic neurochemistry. Positron emission tomography was used to assess changes in the 5HT transporter and 2A receptor binding potential (BP). Functional output of the 5HT system was assessed using prolactin levels. Cocaine-primed reinstatement and cocaine-elicited dopamine overflow were significantly suppressed following chronic fluoxetine treatment. 5HT2A receptor BP was increased in the frontal cortex following treatment while prolactin release was blunted, suggesting desensitization of the 5HT2A receptor. These effects persisted after a 6-week washout period. Measures of pre-synaptic serotonergic function and cocaine self-administration were unaffected. These data demonstrate that acute and chronic fluoxetine treatments exert different effects on cocaine-related behavior. Furthermore, chronic fluoxetine treatment causes alterations in 5HT2A receptors in the frontal cortex that may selectively disrupt cocaine-primed reinstatement. Fluoxetine may not be useful for treatment of ongoing cocaine abuse but may be useful in relapse prevention.

Copyright information:

© 2012 American College of Neuropsychopharmacology

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