Region-specific transcriptional response to chronic nicotine in rat brain.
Even though nicotine has been shown to modulate mRNA expression of a variety of genes, a comprehensive high-throughput study of the effects of nicotine on the tissue-specific gene expression profiles has been lacking in the literature. In this study, cDNA microarrays containing 1117 genes and ESTs were used to assess the transcriptional response to chronic nicotine treatment in rat, based on four brain regions, i.e. prefrontal cortex (PFC), nucleus accumbens (NAs), ventral tegmental area (VTA), and amygdala (AMYG). On the basis of a non-parametric resampling method, an index (called jackknifed reliability index, JRI) was proposed, and employed to determine the inherent measurement error across multiple arrays used in this study. Upon removal of the outliers, the mean correlation coefficient between duplicate measurements increased to 0.978+/-0.0035 from 0.941+/-0.045. Results from principal component analysis and pairwise correlations suggested that brain regions studied were highly similar in terms of their absolute expression levels, but exhibited divergent transcriptional responses to chronic nicotine administration. For example, PFC and NAs were significantly more similar to each other (r=0.7; P<10(-14)) than to either VTA or AMYG. Furthermore, we confirmed our microarray results for two representative genes, i.e. the weak inward rectifier K(+) channel (TWIK-1), and phosphate and tensin homolog (PTEN) by using real-time quantitative RT-PCR technique. Finally, a number of genes, involved in MAPK, phosphatidylinositol, and EGFR signaling pathways, were identified and proposed as possible targets in response to nicotine administration.
Konu O
Department of Pharmacology, University of Tennessee College of Medicine, 874 Union Avenue, Memphis, TN 38163, USA.
Kane
J K
JK
Barrett
T
T
Vawter
M P
MP
Chang
R
R
Ma
J Z
JZ
Donovan
D M
DM
Sharp
B
B
Becker
K G
KG
Li
M D
MD
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D005796:Genes / Q000187:drug effects / Q000502:physiology; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014029:Tobacco Use Disorder / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D025521:Tumor Suppressor Proteins; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
C487530:Kcnk1 protein, rat; D018722:Nicotinic Agonists; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D009538:Nicotine; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase