Abstract
Serotonin 2C receptor (5-HT2CR) 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-HT2CR pre-mRNA undergoes adenosine-to-inosine editing, generating numerous receptor isoforms in brain. As editing influences 5-HT2CR 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-HT2CR mRNA editing and expression in HR and LR phenotypes to investigate the relationship between 5-HT2CR 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-HT2CR 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-HT2CR 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-HT2CR 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.
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Acknowledgements
This work was supported by the National Institute on Drug Abuse grant DA022264 (SD), the VISN3 Mental Illness Research and Education Clinical Center (SD) and the use of facilities at the JJ Peters VA Medical Center, Bronx, NY where SD and YH are Research Health Science Specialists and WB is a Staff Physician. We are grateful to Ms Nayna Patel and Mr Benjamin Chin for their superb technical assistance.
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The authors declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Dracheva, S., Lyddon, R., Barley, K. et al. Editing of Serotonin 2C Receptor mRNA in the Prefrontal Cortex Characterizes High-Novelty Locomotor Response Behavioral Trait. Neuropsychopharmacol 34, 2237–2251 (2009). https://doi.org/10.1038/npp.2009.51
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DOI: https://doi.org/10.1038/npp.2009.51
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