Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factor Bdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.
Gene expression changes in the post-mortem nucleus accumbens of chronic heroin abusers. Overall, little overlap in gene expression profiles was seen between the two drug-abusing cohorts: out of the approximately 39,000 transcripts investigated, the abundance of only 25 was significantly changed in both cocaine and heroin abusers, with nearly one-half of these being altered in opposite directions. 1050 Transcripts had different in abundance between the majority of heroin subjects and their matched controls.
Examination of changes in gene expression induced by repeated administration of the mGlu5 antagonists MPEP and MTEP. Male Wistar rats (n=5 per treatment group) were administered MPEP (10 mg/kg), MTEP (10 mg/kg) or vehicle intraperitoneally twice daily for 5 days.
A list of the 307 genes found to be upregulated or downregulated by ethanol in PFC, VTA or NA of B6 or D2 mice. ID number represents cluster membership from Figure 4.
Authors:
Kerns RT, Ravindranathan A, Hassan S, Cage MP, York T, Sikela JM, Williams RW, Miles MF
Striatum Gene Expression Correlates for ACTI_DIFF_05 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The ACTI_DIFF_05 measures Difference in distance traveled (cm) during the first five min (saline-ethanol) under the domain Ethanol. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Cerebellum Gene Expression Correlates for TAILCLIP_LAT_SEC measured in BXD RI Males obtained using SJUT Cerebellum mRNA M430 (Mar05) RMA. The TAILCLIP_LAT_SEC measures Mechanical Nociception - Tail Clip Test under the domain Pain. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Differentially expressed in the Nucleus accumbens following 24 hr continuous 9.5g/kg/day alcohol drinking vs. water drinking in alcohol preferring rats. Estimated BAC in the alcohol exposed group was > 85mg%. The 406 significanlty different probe sets represent 374 uniquely named genes, with most gene expression differences in the range of 1.1-1.3 fold.
A list of genes whose transcript abundance in the PFC changed significantly 4 hours after an acute dose of ethanol (1.8 g/kg). This list was generated using Fisher's Combined Probability test to analyze saline vs ethanol S-scores across B6 and D2 inbred strains (n=3) and 27 BXD RI lines (n=1). Statistical significance was determined using 1,000 permutations of S-score data and selecting for probe-sets with q-values < 0.05. Aaron Wolen 5-26-10.
Authors:
Wolen AR, Phillips CA, Langston MA, Putman AH, Vorster PJ, Bruce NA, York TP, Williams RW, Miles MF
The production of 12 out of 27 measured factors was induced by CEsHUT including IL-1β, TNF and IL-1Ra. In contrast to sIL-1Ra production, that of IL-1β and TNF was inhibited by HDL, corroborating previous results. In addition, CEsHUT induced monocytes to produce factors involved in their localization, survival and differentiation such as CCL5 (RANTES), CCL2 (MCP-1), interferon-γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage-CSF (M-CSF). The production of the latter was moderate and it was not affected by HDL.
Authors:
Gruaz L, Delucinge-Vivier C, Descombes P, Dayer JM, Burger D
QTL for ethanol withdrawal on Chr10 at Ha1 (98.44 Mbp , Build 37)
Description:
ethanol withdrawal spans 73.44 - 123.44 Mbp (NCBI Build 37) on Chr10. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL for METH responses for home cage activity on Chr10 at D10Mit144 (102.84 Mbp , Build 37)
Description:
METH responses for home cage activity spans 77.84 - 127.84 Mbp (NCBI Build 37) on Chr10. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL for METH responses for body temperature on Chr10 at Kcnc2 (114.10 Mbp , Build 37)
Description:
METH responses for body temperature spans 89.10 - 139.10 Mbp (NCBI Build 37) on Chr10. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
Genes associated with Homo sapiens that interact with the MeSH term 'Azacitidine' (D001374). Incorporates data from 1 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term '5-dihydrocortisone' (C045993). Incorporates data from 1538 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Oryctolagus cuniculus that interact with the MeSH term 'Ionomycin' (D015759). Incorporates data from 6 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'Smoke' (D012906). Incorporates data from 54 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'Fluorouracil' (D005472). Incorporates data from 99 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Sus scrofa that interact with the MeSH term 'deoxynivalenol' (C007262). Incorporates data from 1 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
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