Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
Authors:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
QTL for METH responses for body temperature on Chr19 at Pomc-2 (14.21 Mbp , Build 37)
Description:
METH responses for body temperature spans 0.00 - 39.21 Mbp (NCBI Build 37) on Chr19. 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 Chr19 at Lpc1 (23.27 Mbp , Build 37)
Description:
METH responses for body temperature spans 0.00 - 48.27 Mbp (NCBI Build 37) on Chr19. 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 alcohol preference locus on Chr19 at D19Mit46 (29.54 Mbp , Build 37)
Description:
alcohol preference locus spans 4.54 - 54.54 Mbp (NCBI Build 37) on Chr19. 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 alcohol preference locus on Chr19 at D19Mit46 (29.54 Mbp , Build 37)
Description:
alcohol preference locus spans 4.54 - 54.54 Mbp (NCBI Build 37) on Chr19. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL associated with "alcohol preference locus 23, male specific". This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (33009697)
QTL associated with "alcohol preference locus 24, female specific". This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (33009697)
QTL associated with cytokine induced activation 4. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (46847452)
QTL associated with experimental allergic encephalomyelitis susceptibility 19. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (35392252)
QTL associated with exploratory and excitability QTL 4. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (39514309)
Authors:
Zhang S, Lou Y, Amstein TM, Anyango M, Mohibullah N, Osoti A, Stancliffe D, King R, Iraqi F, Gershenfeld HK
QTL associated with fluctuating asymmetry QTL 10. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (20420342)
Authors:
Zhang S, Lou Y, Amstein TM, Anyango M, Mohibullah N, Osoti A, Stancliffe D, King R, Iraqi F, Gershenfeld HK
QTL associated with hepatocarcinogenesis susceptibility 6. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (44927487)
Authors:
Falvella FS, Pascale RM, Gariboldi M, Manenti G, De Miglio MR, Simile MM, Dragani TA, Feo F
QTL associated with induction of brown adipocytes 4. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (26402805)
QTL associated with kidney weight 1. This interval was obtained by using a fixed interval width of 25 Mbp around the peak marker (55112429)
Authors:
Kim EH, Lee CH, Hyun BH, Suh JG, Oh YS, Namikawa T, Ishikawa A
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