Serotonergic mechanisms involved in the discriminative stimulus, reinforcing and subjective effects of cocaine

Sharon L. Walsh, Kathryn Cunningham

Research output: Contribution to journalArticle

188 Scopus citations


The purpose of the present manuscript is to review the current status of the role of serotonin (5-hydroxytryptamine; 5-HT) systems in the stimulus and reinforcing properties of cocaine in non-humans and the subjective effects of cocaine in humans. Review of the current literature suggests that general enhancement (via precursor administration) or depletion of brain 5-HT content (via neurotoxin administration or tryptophan depletion) impact the reinforcing effects of cocaine in non-humans and its subjective effects in humans. Selective 5-HT reuptake inhibitors (SSRIs) enhance the discriminability of cocaine and decrease cocaine self-administration in animals, although data to the contrary also exist. Studies in humans suggest that SSRIs attenuate the subjective effects of cocaine in humans. Although few drugs with selectivity for 5-HT2 receptors have been studied systematically, a 5-HT2 agonist and several antagonists show some efficacy in enhancing and reducing, respectively, the reinforcing effects of cocaine in non-humans. Limited data from humans suggest that a 5-HT2 antagonist may also decrease the subjective effects of cocaine; thus, 5-HT2 compounds deserve further attention. The majority of studies evaluating the 5-HT3 antagonists have reported negative results across all paradigms. In summary, while the functional significance of 5-HT receptors has not been fully elucidated, these data suggest that changes in serotonergic activity can modulate the effects of cocaine in both animals and humans under a variety of experimental conditions. One commonality among the studies with positive findings is that cocaine effects are only partially modified by 5-HT agents regardless of the direction of change.

Original languageEnglish (US)
Pages (from-to)41-58
Number of pages18
Issue number1
StatePublished - 1997



  • 5-HT(1A)
  • 5-HT
  • 5-HT
  • Cocaine
  • Dopamine (DA)
  • Drug discrimination
  • Human
  • Rat
  • Reinforcing effects
  • Reuptake inhibitor
  • Self-administration
  • Serotonin (5-HT)
  • Stimulus effects
  • Subjective effects

ASJC Scopus subject areas

  • Pharmacology

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