Editing of serotonin 2C receptor mRNA in the prefrontal cortex characterizes high-novelty locomotor response behavioral trait.
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.
Dracheva
Stella
S
James J Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA. Stella.Dracheva@mssm.edu
Lyddon
Rebecca
R
Barley
Kevin
K
Marcus
Sue M
SM
Hurd
Yasmin L
YL
Byne
William M
WM
D000243:Adenosine Deaminase / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism; D010641:Phenotype; D017397:Prefrontal Cortex / Q000502:physiology*; D017393:RNA Editing / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D013223:Statistics as Topic; D017557:Ventral Tegmental Area / Q000378:metabolism
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D044405:Receptor, Serotonin, 5-HT2C; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase