Age-related effects of heroin on gene expression in the hippocampus and striatum of cynomolgus monkeys
Mi Ran Choi , Yeung-Bae Jin , Sol Hee Bang , Chang-Nim Im , Youngjeon Lee , Han-Na Kim , Kyu-Tae Chang , Sang-Rae Lee , Dai-Jin Kim *
1Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea, 2National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea, 3Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea
Received: February 26, 2019; Revised: May 2, 2019; Accepted: May 3, 2019; Published online: May 3, 2019.
© The Korean College of Neuropsychopharmacology. All rights reserved.

Abstract
Objective: The aim of this study was to investigate differentially expressed genes and their functions in the hippocampus and striatum after heroin administration in cynomolgus macaques of different ages.
Methods: Cynomolgus monkeys were divided by age as follows: 1 year (A1, n=2); 3-4 years (A2, n=2); 6-8 years (A3, n=2); and older than 11 years (A4, n=2). After heroin was injected intramuscularly into the monkeys (0.6 mg/kg), we performed large-scale transcriptome profiling in the hippocampus (H) and striatum (S) using RNA-Seq technology. Some genes were validated with RT-qPCR.
Results: In the hippocampus, the gene expression of A1H was similar to that of A4H, while the gene expression of A2H was similar to that of A3H. Genes associated with the MAPK signaling pathway (STMN1, FGF14, and MAPT) and GABAergic synapses (GABBR2 and GAD1) were differentially expressed among control and heroin-treated animals. Differential gene expression between A1S and A4S was the least significant, while differential gene expression between A3S and A2S was the most significant. Genes associated with the neurotrophin signaling pathway (NTRK1 and NGFR), autophagy (ATG5), and dopaminergic synapses in the striatum (AKT1) were differentially expressed among control and heroin-treated animals. Considering that the neurotrophin signaling pathway is related to the survival of neural cells, a decrease in expression of NTRK1 and NGFR could exhibit a negative effect on neuronal survival in the striatum.
Conclusion: These results suggest that even a single heroin exposure can cause differential gene expression in the hippocampus and striatum of nonhuman primates at different ages.
Keywords: Age effect, Heroin, Hippocampus, Nonhuman primates, Striatum, Transcriptome profiling


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