Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.
Intermittent models of alcohol exposure that mimic human patterns of alcohol consumption produce profound physiological and biochemical changes and induce rapid increases in alcohol self-administration. We used high-density oligonucleotide microarrays to investigate gene expression changes during chronic intermittent alcohol exposure in three brain regions that receive mesocorticolimbic dopaminergic projections and that are believed to be involved in alcohol's reinforcing actions: the medial prefrontal cortex, the nucleus accumbens and the amygdala. An independent replication of the experiment was used for RT-PCR validation of the microarray results. The protein kinase A inhibitor alpha (PKI-alpha, Pkia), a member of the endogenous PKI family implicated in reducing nuclear PKA activity, was found to be increased in all three regions tested. Conversely, we observed a downregulation of the expression of several PKA-regulated transcripts in one or more of the brain regions studied, including the activity and neurotransmitter-regulated early gene (Ania) - 1, -3, -7, -8, the transcription factors Egr1 and NGFI-B (Nr4a1) and the neuropeptide NPY. Reduced expression of PKA-regulated genes in mesocorticolimbic projection areas may have motivational significance in the rapid increase in alcohol self-administration induced by intermittent alcohol exposure.
Repunte-Canonigo
Vez
V
Molecular and Integrative Neuroscience Department and San Diego Alcohol, Research Center, The Scripps Research Institute, La Jolla, CA 92103, USA.
Lutjens
Robert
R
van der Stap
Lena D
LD
Sanna
Pietro Paolo
PP
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004334:Drug Administration Schedule; D051766:Early Growth Response Protein 1 / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology*; D000072233:Homer Scaffolding Proteins; D017874:Immediate-Early Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D020932:Nerve Growth Factor / Q000235:genetics; D009478:Neuropeptide Y / Q000235:genetics; D009714:Nucleus Accumbens / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar
D002352:Carrier Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D000072233:Homer Scaffolding Proteins; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D020033:Protein Isoforms; D012333:RNA, Messenger; C015482:protein kinase modulator; D000431:Ethanol; D020932:Nerve Growth Factor; D017868:Cyclic AMP-Dependent Protein Kinases