Functional status of the serotonin 5-HT 2C receptor (5-HT 2C R) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence

Noelle C. Anastasio, Sonja J. Stutz, Robert G. Fox, Robert M. Sears, Ronald B. Emeson, Ralph J. Dileone, Richard T. O'Neil, Latham H. Fink, Dingge Li, Thomas A. Green, F. Gerard Moeller, Kathryn A. Cunningham

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT 2C receptor (5-HT 2C R) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT 2C R functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT 2C R macromolecular protein complex, and editing of the 5-HT 2C R pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT 2C R membrane protein levels concomitant with higher levels of 5-HT 2C R:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT 2C R mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT 2C R induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT 2C R tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT 2C R functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.

Original languageEnglish (US)
Pages (from-to)360-372
Number of pages13
Issue number2
StatePublished - Jan 2014


  • 5-HT receptor
  • RNA editing
  • cocaine
  • cue reactivity
  • impulsive action
  • prefrontal cortex

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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