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Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine.

Grice DE, Reenilä I, Männistö PT, Brooks AI, Smith GG, Golden GT, Buxbaum JD, Berrettini WH - BMC Genomics (2007)

Bottom Line: Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences.One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse.Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Psychiatry, University of Medicine and Dentistry of New Jersey/New Jersey Medical School, Newark, NJ, USA. dorothy.grice@gmail.com

ABSTRACT

Background: The mouse C57BL/6 (C57) and DBA/2J (DBA) inbred strains differ substantially in many aspects of their response to drugs of abuse. The development of microarray analyses represents a genome-wide method for measuring differences across strains, focusing on expression differences. In the current study, we carried out microarray analysis in C57 and DBA mice in the nucleus accumbens of drug-naïve and morphine-treated animals.

Results: We identified mRNAs with altered expression between the two strains. We validated the mRNA expression changes of several such mRNAs, including Gnb1, which has been observed to be regulated by several drugs of abuse. In addition, we validated alterations in the enzyme activity of one mRNA product, catechol-O-methyltransferase (Comt). Data mining of expression and behavioral data indicates that both Gnb1 and Comt expression correlate with aspects of drug response in C57/DBA recombinant inbred strains. Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences. These analyses identified axon guidance genes, particularly the semaphorins, as showing altered expression in the presence of morphine, and plasticity genes as showing altered expression across strains. Pathway analysis of genes showing strain by treatment interaction suggest that the phosphatidylinositol signaling pathway may represent an important difference between the strains as related to morphine exposure.

Conclusion: mRNAs with differing expression between the two strains could potentially contribute to strain-specific responses to drugs of abuse. One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse. Similarly, a role for Gnb1 in responses to multiple drugs of abuse is supported by expression data from our study and from other studies. Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains.

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Enzymatic assay of Comt activity in DBA and C57 strains. Nucleus accumbens (NAC), amygdala (AMY), and frontal cortex (FC) were dissected from DBA and C57 mice, and Comt activity was determined in homogenates, as described in the methods. *, P = 0.01; **, P = 0.002.
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Figure 2: Enzymatic assay of Comt activity in DBA and C57 strains. Nucleus accumbens (NAC), amygdala (AMY), and frontal cortex (FC) were dissected from DBA and C57 mice, and Comt activity was determined in homogenates, as described in the methods. *, P = 0.01; **, P = 0.002.

Mentions: The correlation of Comt expression with two indices of morphine effect suggested a possible relationship between these two measures in mice. As mRNA levels do not always correlate with protein levels and protein activity, we next sought to determine whether Comt activity differed in brain extracts from C57 and DBA mice. NAC, amygdala (AMY), and frontal cortex (FC) were dissected from DBA and C57 mice and Comt activity was then determined in homogenates. Comt activity was modestly, but significantly, reduced in NAC (p = 0.01) and FC (p = 0.002) of DBA mice, as compared to C57 mice (Figure 2).


Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine.

Grice DE, Reenilä I, Männistö PT, Brooks AI, Smith GG, Golden GT, Buxbaum JD, Berrettini WH - BMC Genomics (2007)

Enzymatic assay of Comt activity in DBA and C57 strains. Nucleus accumbens (NAC), amygdala (AMY), and frontal cortex (FC) were dissected from DBA and C57 mice, and Comt activity was determined in homogenates, as described in the methods. *, P = 0.01; **, P = 0.002.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851712&req=5

Figure 2: Enzymatic assay of Comt activity in DBA and C57 strains. Nucleus accumbens (NAC), amygdala (AMY), and frontal cortex (FC) were dissected from DBA and C57 mice, and Comt activity was determined in homogenates, as described in the methods. *, P = 0.01; **, P = 0.002.
Mentions: The correlation of Comt expression with two indices of morphine effect suggested a possible relationship between these two measures in mice. As mRNA levels do not always correlate with protein levels and protein activity, we next sought to determine whether Comt activity differed in brain extracts from C57 and DBA mice. NAC, amygdala (AMY), and frontal cortex (FC) were dissected from DBA and C57 mice and Comt activity was then determined in homogenates. Comt activity was modestly, but significantly, reduced in NAC (p = 0.01) and FC (p = 0.002) of DBA mice, as compared to C57 mice (Figure 2).

Bottom Line: Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences.One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse.Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Psychiatry, University of Medicine and Dentistry of New Jersey/New Jersey Medical School, Newark, NJ, USA. dorothy.grice@gmail.com

ABSTRACT

Background: The mouse C57BL/6 (C57) and DBA/2J (DBA) inbred strains differ substantially in many aspects of their response to drugs of abuse. The development of microarray analyses represents a genome-wide method for measuring differences across strains, focusing on expression differences. In the current study, we carried out microarray analysis in C57 and DBA mice in the nucleus accumbens of drug-naïve and morphine-treated animals.

Results: We identified mRNAs with altered expression between the two strains. We validated the mRNA expression changes of several such mRNAs, including Gnb1, which has been observed to be regulated by several drugs of abuse. In addition, we validated alterations in the enzyme activity of one mRNA product, catechol-O-methyltransferase (Comt). Data mining of expression and behavioral data indicates that both Gnb1 and Comt expression correlate with aspects of drug response in C57/DBA recombinant inbred strains. Pathway analysis was carried out to identify pathways showing significant alterations as a result of treatment and/or due to strain differences. These analyses identified axon guidance genes, particularly the semaphorins, as showing altered expression in the presence of morphine, and plasticity genes as showing altered expression across strains. Pathway analysis of genes showing strain by treatment interaction suggest that the phosphatidylinositol signaling pathway may represent an important difference between the strains as related to morphine exposure.

Conclusion: mRNAs with differing expression between the two strains could potentially contribute to strain-specific responses to drugs of abuse. One such mRNA is Comt and we hypothesize that altered expression of Comt may represent a potential mechanism for regulating the effect of, and response to, multiple substances of abuse. Similarly, a role for Gnb1 in responses to multiple drugs of abuse is supported by expression data from our study and from other studies. Finally, the data support a role for semaphorin signaling in morphine effects, and indicate that altered expression of genes involved in phosphatidylinositol signaling and plasticity might also affect the altered drug responses in the two strains.

Show MeSH
Related in: MedlinePlus