Editing of serotonin 2C receptor mRNA in the prefrontal cortex characterizes high-novelty locomotor response behavioral trait

Neuropsychopharmacology. 2009 Sep;34(10):2237-51. doi: 10.1038/npp.2009.51. Epub 2009 Jun 3.


Serotonin 2C receptor (5-HT(2C)R) exerts a major inhibitory influence on dopamine (DA) neurotransmission within the mesocorticolimbic DA pathway that is implicated in drug reward and goal-directed behaviors. 5-HT(2C)R pre-mRNA undergoes adenosine-to-inosine editing, generating numerous receptor isoforms in brain. As editing influences 5-HT(2C)R activity, individual differences in editing might influence dopaminergic function and, thereby, contribute to interindividual vulnerability to drug addiction. Liability to drug-related behaviors in rats can be predicted by their level of motor activity in response to a novel environment. Rats with a high locomotor response (high responders; HRs) exhibit enhanced acquisition and maintenance of drug self-administration compared to rats with a low response (low responders; LRs). We here examined 5-HT(2C)R mRNA editing and expression in HR and LR phenotypes to investigate the relationship between 5-HT(2C)R function and behavioral traits relevant to drug addiction vulnerability. Three regions of the mesocorticolimbic circuitry (ventral tegmental area (VTA), nucleus accumbens (NuAc) shell, and medial prefrontal cortex (PFC)) were examined. 5-HT(2C)R mRNA expression and editing were significantly higher in the NuAc shell compared with both the PFC and VTA, implying significant differences in function (including constitutive activity) among 5-HT(2C)R neuronal populations within the circuitry. The regional differences in editing could, at least in part, arise from the variations in expression levels of the editing enzyme, ADAR2, and/or from the variations in the ADAR2/ADAR1 ratio observed in the study. No differences in the 5-HT(2C)R expression were detected between the behavioral phenotypes. However, editing was higher in the PFC of HRs vs LRs, implicating this region in the pathophysiology of drug abuse liability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Animals
  • Behavior, Animal / physiology
  • Exploratory Behavior / physiology*
  • Gene Expression Regulation / physiology*
  • Gene Knock-In Techniques / methods
  • Humans
  • Male
  • Nucleus Accumbens / metabolism
  • Phenotype
  • Prefrontal Cortex / physiology*
  • RNA Editing / physiology*
  • RNA, Messenger / genetics*
  • RNA-Binding Proteins
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2C / genetics*
  • Statistics as Topic
  • Ventral Tegmental Area / metabolism


  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptor, Serotonin, 5-HT2C
  • ADARB1 protein, human
  • Adenosine Deaminase