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.
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
High-density filter-based cDNA microarrays were used to assess differential expression of genes in the dorsal hippocampus of rats treated with 12% ethanol or tap water for 15 months. Following treatment, an analysis of ethanol-treated versus control rats was done.These are genes that were downregulated during the chronic ethanol treatment.
Hippocampus Gene Expression Correlates for PCT_TIME_OPEN measured in BXD RI Females & Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The PCT_TIME_OPEN measures Percentage of time into open arms of plus maze 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
Hippocampus Gene Expression Correlates for TIME_MID_SAL measured in BXD RI Females & Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The TIME_MID_SAL measures Amount of time in middle of plus maze 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
Hippocampus Gene Expression Correlates for TIME_OPEN_SAL measured in BXD RI Females & Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The TIME_OPEN_SAL measures Amount of time in open arms of plus maze 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
Hippocampus Gene Expression Correlates for AMCNT30 measured in BXD RI Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The AMCNT30 measures Morphine photocell counts minutes 15-30 under the domain Morphine. 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
Hippocampus Gene Expression Correlates for AMCNT45 measured in BXD RI Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The AMCNT45 measures Morphine photocell counts minutes 30-45 under the domain Morphine. 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
Hippocampus Gene Expression Correlates for AMCNT60 measured in BXD RI Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The AMCNT60 measures Morphine photocell counts minutes 45-60 under the domain Morphine. 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
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
cocaine related behavior 3 (Cocrb3) spans 114.482445 - 164.482445 Mbp (NCBI Build 37) on Chr 2. Obtained from MGI (http://www.informatics.jax.org) by searching for QTLs containing the keyword .
QTL for cocaine related behavior on Chr2 at D2Byu3 (139.48 Mbp , Build 37)
Description:
cocaine related behavior spans 114.48 - 164.48 Mbp (NCBI Build 37) on Chr2. 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 ethanol induced locomotion on Chr2 at NA (141.12 Mbp , Build 37)
Description:
ethanol induced locomotion spans 116.12 - 166.12 Mbp (NCBI Build 37) on Chr2. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
Authors:
Hitzemann R, Demarest K, Koyner J, Cipp L, Patel N, Rasmussen E, McCaughran J Jr
QTL for high-dose ethanol actions on Chr2 at D2Mit21 (159.38 Mbp , Build 37)
Description:
high-dose ethanol actions spans 134.38 - 184.38 Mbp (NCBI Build 37) on Chr2. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
Authors:
Erwin VG, Markel PD, Johnson TE, Gehle VM, Jones BC
QTL for METH responses for climbing on Chr2 at D2Mc1 (162.34 Mbp , Build 37)
Description:
METH responses for climbing spans 137.34 - 187.34 Mbp (NCBI Build 37) on Chr2. 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 nicotine sensitivity on Chr2 at D2Mit311 (162.39 Mbp , Build 37)
Description:
nicotine sensitivity spans 137.39 - 187.39 Mbp (NCBI Build 37) on Chr2. 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 'Electrolytes' (D004573). Incorporates data from 109 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 'Dexamethasone' (D003907). Incorporates data from 14 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
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