Ethanol activates cAMP response element-mediated gene expression in select regions of the mouse brain

Brain Res. 2006 Aug 23;1106(1):63-71. doi: 10.1016/j.brainres.2006.05.107. Epub 2006 Jul 18.

Abstract

The specific brain regions that contribute to behavioral changes produced by ethanol are not clearly understood. We know that cAMP-PKA signaling has been strongly implicated in the CNS effects of ethanol. Ethanol promotes activation and translocation of the PKA catalytic subunit (Calpha) into the nucleus in cell lines and primary neuronal cultures. PKA Calpha translocation to the nucleus is followed by cAMP Response Element protein phosphorylation (pCREB) and cAMP Response Element (CRE)-mediated gene expression. Here, we use X-gal histochemistry to map CRE-mediated gene transcription in the brain of CRE-lacZ transgenic mice following ethanol injection.

Results: 3 h after i.p. ethanol injection (3.2 g/kg, 16% wt/vol.), the number of X-gal positive cells was increased in the nucleus accumbens (202 +/- 63 cells/field compared to 71 +/- 47 cells/field in saline injected controls, P < 0.05 by paired t-test, n = 10). Similar increases were found in other mesolimbic areas and brain regions associated with rewarding and addictive responses. These include: prefrontal cortex, lateral and medial septum, basolateral amygdala, paraventricular and anterior hypothalamus, centromedial thalamus, CA1 region of hippocampus and dentate gyrus, substantia nigra pars compacta, ventral tegmental area, geniculate nucleus and the superior colliculus.

Conclusion: these results confirm and extend current concepts that ethanol stimulates cAMP-PKA signaling in brain regions involved in CNS responses to ethanol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol-Induced Disorders, Nervous System / genetics
  • Alcohol-Induced Disorders, Nervous System / metabolism*
  • Alcohol-Induced Disorders, Nervous System / physiopathology
  • Animals
  • Brain / anatomy & histology
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Chemistry / drug effects*
  • Brain Chemistry / genetics
  • Central Nervous System Depressants / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Ethanol / pharmacology*
  • Female
  • Galactosides
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Genes, Reporter / drug effects
  • Genes, Reporter / physiology
  • Indoles
  • Lac Operon / drug effects
  • Lac Operon / genetics
  • Limbic System / anatomy & histology
  • Limbic System / drug effects
  • Limbic System / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Reward
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Central Nervous System Depressants
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Galactosides
  • Indoles
  • RNA, Messenger
  • Ethanol
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • 5-bromo-4-chloro-3-indolyl beta-galactoside