Age-related Effects of Heroin on Gene Expression in the Hippocampus and Striatum of Cynomolgus Monkeys

Abstract

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 to 4 years (A2, n = 2); 6 to 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 sequencing technology. Some genes were validated with real-time quantitative PCR. 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 mitogen-activated protein kinase signaling pathway (STMN1, FGF14, and MAPT) and -aminobutyric acid-ergic 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 (AKT1) in the striatum were differentially expressed among control and heroin-treated animals. 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.

Identification of Morphine and Heroin-Treatment in Mice Using Metabonomics

“…Opiate-use disorders include dependence and addiction, and addiction represents the most serious form of the disorder [ 12 ]. In addition to changes in the basal nucleus and brain regions such as the nucleus accumbens [ 13 , 14 ], hippocampus [ 15 , 16 ] and amygdala [ 17 , 18 ], heroin or morphine addiction also involves reward [ 19 , 20 ], motivation [ 21 , 22 ], learning and memory [ 23 , 24 ] and changes the coupling among salience, default mode, and executive control networks [ 25 , 26 ]. However, heroin or morphine addiction is an uncontrolled, chronic, and recurrent encephalopathy that lacks specific and characteristic biomarkers for diagnosis and treatment.…”

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

“…Not surprisingly, a large majority focused on the mesocorticolimbic dopaminergic pathway: the NAc (21 articles [8,22,26,28–30,32,40–53]), frontal cortex (13 articles [8,25,27,29,51,54–61]), whole/unspecified striatal complex (11 articles [24,33,62–70]), dorsal striatum (7 articles [8,30,48–50,71,72]) and ventral tegmental area (VTA, 5 articles [28,51,73–75]). Other regions included the spinal cord (7 articles [62,76– 81]); hippocampus (5 articles [8,63,82–84]); amygdala (3 articles [8,85,86]); locus coeruleus [74, 87], ventral midbrain [42, 88], hypothalamus [89, 90], whole brain with [91] or without [92] cerebellum (1 each); periaqueductal gray matter [93], pituitary gland [90], arcuate nucleus [94], nucleus of the tractus solitarius [31], brainstem [23], cerebellum [84] or dorsal root ganglia [95] (DRG, 1 each). Below, we briefly describe the rationale for studying such diverse structures.…”

“…Not surprisingly, a large majority focused on the mesocorticolimbic dopaminergic pathway: the NAc (21 articles [8,22,26,[28][29][30]32,[40][41][42][43][44][45][46][47][48][49][50][51][52][53]), frontal cortex (13 articles [8,25,27,29,51,[54][55][56][57][58][59][60][61]), whole/unspecified striatal complex (11 articles [24,33,[62][63][64][65][66][67][68][69][70]), dorsal striatum (7 articles [8,30,[48][49][50]…”

Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder

“…This is an important mechanism for regulating activity in the hypothalamic-neurohypophysial system, which is heavily influenced by voltage-gated Ca 2+ channel density 83 and impacts the release of oxytocin 84 ; however, there is very little published data on the role of CACNG3 in the brain. Two recent studies implicated CACNG3 in addiction 85 and memory deficits 86 in the hippocampus, both of which have also been associated with disruptions to oxytocin signaling. These findings point towards a potential role for CACNG3 in the activation of oxytocin-associated neurons, its broader overlap with glutamatergic signaling, and modulation of OT release via Ca 2+ depolarization, which might contribute to the increased plasma OT levels observed in the five C-allele carriers of rs7186490.…”