Changes in the expression of transthyretin and protein kinase Cγ genes in the prefrontal cortex in response to naltrexone.
Naltrexone, an opioid receptor antagonist, has been approved for clinical use in the treatment of alcohol dependence. In the present study, we examined the underlying mechanisms of naltrexone by investigating the pharmacogenomic variations in the brain regions associated with alcohol consumption. A complementary DNA microarray analysis was used to profile gene expression changes in the hippocampus and prefrontal cortex (PFC) of C57BL/6 mice injected with naltrexone following ethanol treatment. Intraperitoneal administration of 200μl (16mg/kg) of naltrexone for 4 weeks caused alterations in the expression of a wide range of hippocampal (394) and PFC (566) genes in ethanol-treated mice. Ingenuity Pathway Analysis (IPA) software was used to search for biological pathways and interrelationships between gene networks in the subsets of candidate genes that were altered in the naltrexone-treated PFC and hippocampus. We found gene networks associated with cell morphology, cell death, nervous system development and function, and neurological disease. Confirmation studies using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that the expression of transthyretin (TTR) and protein kinase C (PKC)γ were increased in the PFC but not in the hippocampus of naltrexone-treated mice. In conclusion, the present study demonstrates a pharmacogenomic response to naltrexone in the brains of ethanol-consuming mice. These findings provide a basis for conducting pharmacogenetic research on the effect of naltrexone in specific brain areas, which would enhance our understanding of the underlying causes and possible treatments of alcohol use disorders.
Department of Neuropsychiatry, Konkuk University School of Medicine, Seoul, Republic of Korea.
Jaehak
J
Yu
Debasish
D
Halder
Mi Na
MN
Baek
Nando Dulal
ND
Das
Mi Ran
MR
Choi
Dong Yul
DY
Oh
Ihn Geun
IG
Choi
Kyoung Hwa
KH
Jung
Young Gyu
YG
Chai
D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D015870:Gene Expression / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011228:Prealbumin / Q000096:biosynthesis* / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009292:Narcotic Antagonists; D011228:Prealbumin; D009271:Naltrexone; C087857:protein kinase C gamma; D011493:Protein Kinase C