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 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 Green, F. Gerard Moeller, Kathryn Cunningham

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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
JournalNeuropsychopharmacology
Volume39
Issue number2
DOIs
StatePublished - Jan 2014

Fingerprint

Cocaine-Related Disorders
Serotonin
Phenotype
Recurrence
Cues
Cocaine
Prefrontal Cortex
Drive
serotonin 5 receptor
Post-Synaptic Density
Multiprotein Complexes
Behavior Control
Self Administration
Impulsive Behavior
RNA Precursors
Population
Reaction Time
Rodentia
Protein Isoforms
Membrane Proteins

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Functional status of the serotonin 5-HT 2C receptor (5-HT 2C R) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. / Anastasio, Noelle; Stutz, Sonja J.; Fox, Robert G.; Sears, Robert M.; Emeson, Ronald B.; Dileone, Ralph J.; O'Neil, Richard T.; Fink, Latham H.; Li, Dingge; Green, Thomas; Gerard Moeller, F.; Cunningham, Kathryn.

In: Neuropsychopharmacology, Vol. 39, No. 2, 01.2014, p. 360-372.

Research output: Contribution to journalArticle

Anastasio, Noelle ; Stutz, Sonja J. ; Fox, Robert G. ; Sears, Robert M. ; Emeson, Ronald B. ; Dileone, Ralph J. ; O'Neil, Richard T. ; Fink, Latham H. ; Li, Dingge ; Green, Thomas ; Gerard Moeller, F. ; Cunningham, Kathryn. / Functional status of the serotonin 5-HT 2C receptor (5-HT 2C R) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. In: Neuropsychopharmacology. 2014 ; Vol. 39, No. 2. pp. 360-372.
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