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

Dracheva S, Lyddon R, Barley K, Marcus SM, Hurd YL, Byne WM - Neuropsychopharmacology (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: James J Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA. Stella.Dracheva@mssm.edu

ABSTRACT
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.

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Analysis of the ADAR1 and ADAR2 mRNA expressionmRNA expression was measured by qPCR. Shown are Means±SEM. Two different TaqMan assays were employed to distinguish between the ADAR2 transcripts that encode functional (ADAR2f) and truncated non-functional (ADAR2nonf) proteins. ADAR1, ADAR2f, and ADAR2nonf expression levels were significantly different between pairs of regions (all p values <0.0001), but did not differ between HRs and LRs in any region.
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Figure 5: Analysis of the ADAR1 and ADAR2 mRNA expressionmRNA expression was measured by qPCR. Shown are Means±SEM. Two different TaqMan assays were employed to distinguish between the ADAR2 transcripts that encode functional (ADAR2f) and truncated non-functional (ADAR2nonf) proteins. ADAR1, ADAR2f, and ADAR2nonf expression levels were significantly different between pairs of regions (all p values <0.0001), but did not differ between HRs and LRs in any region.

Mentions: The repeated measures analysis showed very significant differences among regions for all transcripts and for the ADAR2f/ADAR1 ratio (5-HT2CRsp1, F=1115.17; df=1.47, 46.93; p<0.0001; 5-HT2CRsp2, F=1086.12; df=1.69, 53.92; p<0.0001; ADAR1, F=83.23; df=1.85, 59.14; p<0.0001; ADAR2f, F=239.89; df=1.48, 47.27; p<0.0001; ADAR2nonf, F=298.94; df=1.29, 41.29; p<0.0001; ADAR2f/ADAR1 ratio, F=27.86; df=1.79, 57.23; p<0.0001), but the differences between HRs and LRs and phenotype by region interaction were not significant. Similarly, the differences between HRs and LRs were not significant in any region, but the differences between pairs of regions (PFC vs. NuAc shell, PFC vs. VTA, and VTA vs. NuAc shell) were highly significant for all transcripts: (5-HT2CRsp1, all t values ≥16.03, all p values <0.0001; 5-HT2CRsp2, all t values ≥ 11.79, all p values <0.0001; ADAR1, all t values ≥ 6.11, all p values <0.0001; ADAR2f, all t values ≥9.96, all p values <0.0001; ADAR2nonf, all t values ≥ 13.70, all p values <0.0001 Figs. 4 and 5). The ADAR2f/ADAR1 ratios were significantly different between the NuAc shell and the two other regions (all t values ≥5.83, all p values <0.0001), but did not differ between the PFC and VTA (Fig. 5).


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

Dracheva S, Lyddon R, Barley K, Marcus SM, Hurd YL, Byne WM - Neuropsychopharmacology (2009)

Analysis of the ADAR1 and ADAR2 mRNA expressionmRNA expression was measured by qPCR. Shown are Means±SEM. Two different TaqMan assays were employed to distinguish between the ADAR2 transcripts that encode functional (ADAR2f) and truncated non-functional (ADAR2nonf) proteins. ADAR1, ADAR2f, and ADAR2nonf expression levels were significantly different between pairs of regions (all p values <0.0001), but did not differ between HRs and LRs in any region.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2735076&req=5

Figure 5: Analysis of the ADAR1 and ADAR2 mRNA expressionmRNA expression was measured by qPCR. Shown are Means±SEM. Two different TaqMan assays were employed to distinguish between the ADAR2 transcripts that encode functional (ADAR2f) and truncated non-functional (ADAR2nonf) proteins. ADAR1, ADAR2f, and ADAR2nonf expression levels were significantly different between pairs of regions (all p values <0.0001), but did not differ between HRs and LRs in any region.
Mentions: The repeated measures analysis showed very significant differences among regions for all transcripts and for the ADAR2f/ADAR1 ratio (5-HT2CRsp1, F=1115.17; df=1.47, 46.93; p<0.0001; 5-HT2CRsp2, F=1086.12; df=1.69, 53.92; p<0.0001; ADAR1, F=83.23; df=1.85, 59.14; p<0.0001; ADAR2f, F=239.89; df=1.48, 47.27; p<0.0001; ADAR2nonf, F=298.94; df=1.29, 41.29; p<0.0001; ADAR2f/ADAR1 ratio, F=27.86; df=1.79, 57.23; p<0.0001), but the differences between HRs and LRs and phenotype by region interaction were not significant. Similarly, the differences between HRs and LRs were not significant in any region, but the differences between pairs of regions (PFC vs. NuAc shell, PFC vs. VTA, and VTA vs. NuAc shell) were highly significant for all transcripts: (5-HT2CRsp1, all t values ≥16.03, all p values <0.0001; 5-HT2CRsp2, all t values ≥ 11.79, all p values <0.0001; ADAR1, all t values ≥ 6.11, all p values <0.0001; ADAR2f, all t values ≥9.96, all p values <0.0001; ADAR2nonf, all t values ≥ 13.70, all p values <0.0001 Figs. 4 and 5). The ADAR2f/ADAR1 ratios were significantly different between the NuAc shell and the two other regions (all t values ≥5.83, all p values <0.0001), but did not differ between the PFC and VTA (Fig. 5).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: James J Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA. Stella.Dracheva@mssm.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus