Editing of Serotonin 2C Receptor mRNA in the Prefrontal Cortex Characterizes High Novelty Locomotor Response Behavioral Trait

James J Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 07/2009; 34(10):2237-51. DOI: 10.1038/npp.2009.51
Source: PubMed


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. Because editing influences 5-HT2CR efficacy, individual differences in editing might influence dopaminergic function and, thereby, contribute to inter-individual vulnerability to drug addiction.
Liability to drug-related behaviors in rats can be predicted by the 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). Here we examined 5-HT2CR mRNA editing and expression in HR and LR phenotypes in order 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 was significantly higher in NuAc shell compared to both 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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    • "The distribution of HTR2C isoforms is remarkably diverse and dependent upon the neuroanatomical region under investigation [14]. In general, the evidence for editing patterns influencing behaviour has been replicated in studies of material collected from the (pre)frontal cortex in both humans [30] and rat [17,18,20]. All of these papers support a role for the gene in anxiety related behaviours, including some forms of aggression. "
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    ABSTRACT: The serotonin pathways have been implicated in behavioural phenotypes in a number of species, including human, rat, mouse, dog and chicken. Components of the pathways, including the receptors, are major targets for drugs used to treat a variety of physiological and psychiatric conditions in humans. In our previous studies we have identified genetic loci potentially contributing to maternal infanticide in pigs, which includes a locus on the porcine X chromosome long arm. The serotonin receptor HTR2C maps to this region, and is therefore an attractive candidate for further study based on its function and its position in the genome. In this paper we describe the structure of the major transcripts produced from the porcine HTR2C locus using cDNA prepared from porcine hypothalamic and pooled total brain samples. We have confirmed conservation of sites altered by RNA editing in other mammalian species, and identified polymorphisms in the gene sequence. Finally, we have analysed expression and editing of HTR2C in hypothalamus samples from infanticidal and control animals. The results confirm that although the expression of the long transcriptional variant of HTR2C is raised in infanticidal animals, the overall patterns of editing in the hypothalamus are similar between the two states.Sequences associated with the cDNA and genomic structures of HTR2C reported in this paper are deposited in GenBank under accession numbers FR720593, FR720594 and FR744452.
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    • "Transcripts encoding the 5HT 2C receptor can be modified by five A-to-I editing events (sites A-E) to generate as many as 24 protein isoforms that differ by up to three amino acids within the predicted second intracellular loop of the receptor, a region involved in receptor:G-protein coupling (Burns et al., 1997; Pin et al., 1994). Though initial sequence analyses of cDNAs isolated from dissected rat and human brains predicted the region-specific expression of as many as 12 major 5HT 2C receptor isoforms encoded by eighteen distinct RNA species (Burns et al., 1997; Niswender et al., 1999), more recent studies identified the expression of 26 of the 32 possible mRNA isoforms and determined that only 4-6 of these mRNAs represent more than 5% of total 5HT 2C transcripts in rats and humans, respectively (Dracheva et al., 2009). Alterations in 5HT 2C receptor editing have been observed in suicide victims with a history of major depression, schizophrenia, or bipolar disorder (Dracheva et al., 2008; Gurevich et al., 2002; Iwamoto and Kato, 2003; Niswender et al., 2001) and in response to antidepressant and antipsychotic treatment (Englander et al., 2005; Gurevich et al., 2002; Sodhi et al., 2005). "
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    ABSTRACT: RNA transcripts encoding the 2C-subtype of serotonin (5HT(2C)) receptor undergo up to five adenosine-to-inosine editing events to encode twenty-four protein isoforms. To examine the effects of altered 5HT(2C) editing in vivo, we generated mutant mice solely expressing the fully-edited (VGV) isoform of the receptor. Mutant animals present phenotypic characteristics of Prader-Willi syndrome (PWS) including a failure to thrive, decreased somatic growth, neonatal muscular hypotonia, and reduced food consumption followed by post-weaning hyperphagia. Though previous studies have identified alterations in both 5HT(2C) receptor expression and 5HT(2C)-mediated behaviors in both PWS patients and mouse models of this disorder, to our knowledge the 5HT(2C) gene is the first locus outside the PWS imprinted region in which mutations can phenocopy numerous aspects of this syndrome. These results not only strengthen the link between the molecular etiology of PWS and altered 5HT(2C) expression, but also demonstrate the importance of normal patterns of 5HT(2C) RNA editing in vivo.
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    • "For example, the 5-HT 2C R is localized to (Mengod et al. 1990; Liu et al. 2007) and controls the excitability of neurons in the prefrontal cortex (PFC) (Carr et al. 2002; Calcagno et al. 2009). Localized stimulation of the PFC 5-HT 2C R has been observed to suppress the hypermotility, discriminative stimulus effects and reinstatement of selfadministration of psychostimulants (Filip and Cunningham 2003; Pentkowski and Neisewander 2008; Leggio et al. 2009) while changes in expression profiles for the 5- HT 2C R in PFC has been linked to addiction vulnerability (Dracheva et al. 2009) and schizophrenia (Dracheva et al. 2003). In contrast, a depression-like phenotype in rats is associated with decrements in 5-HT 2C R protein in motor cortex (Leventopoulos et al. 2009), a cortical region essential for the translation of biologically-relevant stimuli into adaptive motor responses (Kosten et al. 2006). "
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    Full-text · Article · Mar 2010 · Journal of Neurochemistry
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