Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes

Abstract

Repeated nicotine exposure leads to sensitization (SST) and enhances self-administration (SA) in rodents. However, the molecular basis of nicotine SST and SA and their biological relevance to the mounting genome-wide association study (GWAS) loci of human addictive behaviors are poorly understood. Considering a gateway drug role of nicotine, we modeled nicotine SST and SA in F1 progeny of inbred rats (F344/BN) and conducted integrative genomics analyses. We unexpectedly observed male-specific nicotine SST and a parental effect of SA only present in paternal F344 crosses. Transcriptional profiling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) core and shell further revealed sex- and brain region-specific transcriptomic signatures of SST and SA. We found that genes associated with SST and SA were enriched for those related to synaptic processes, myelin sheath, and tobacco use disorder or chemdependency. Interestingly, SST-associated genes were often downregulated in male VTA but upregulated in female VTA, and strongly enriched for smoking GWAS risk variants, possibly explaining the male-specific SST. For SA, we found widespread region-specific allelic imbalance of expression (AIE), of which genes showing AIE bias toward paternal F344 alleles in NAc core were strongly enriched for SA-associated genes and for GWAS risk variants of smoking initiation, likely contributing to the parental effect of SA. Our study suggests a mechanistic link between transcriptional changes underlying the NIC SST and SA and human nicotine addiction, providing a resource for understanding the neurobiology basis of the GWAS findings on human smoking and other addictive phenotypes.

Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

“…Such transcriptional convergence between these two conditions could represent shared withdrawal-associated changes in the NAc despite the extinction training. Nonetheless, a close look at the distribution of statistically significant DEGs, upstream regulators, and biological functions highlights clear transcriptomic differences for the NAc core and shell between these two conditions, as previously suggested 15,17,59,93 . Some of these differences could reflect contextual withdrawal differences, but importantly we incorporated corresponding saline controls that account for the context, cues, and lever-associated stimuli independent of the drug in this study.…”

Phosphorylation of Neurofilament Light Chain in the VLO Is Correlated with Morphine-Induced Behavioral Sensitization in Rats

“…In rodents, behavioral sensitization is characterized by more robust psychomotor development following the same or smaller dose of drug challenge after repeated exposure to drugs. Behavioral sensitization involves functionally distinct phases, such as the development phase, transfer phase and expression phase, and specific brain regions may drive these different phases [1,2]. The ventrolateral orbital cortex (VLO), a major area within the orbitofrontal cortex (OFC), has been implicated in morphine-related addictive phenotypes [3].…”

Detection of Parent-of-Origin Effects for the Variants Associated With Behavioral Disinhibition in the MCTFR Data

“… Strauch et al (2005) used 93 Caucasian pedigrees of the Collaborative Study on the Genetics of Alcoholism dataset and found that some loci on Chromosomes 1, 2, 10, 12, 13, 15 and 21 have paternal imprinting on alcohol dependence, and a tendency to maternal imprinting was observed at two loci on Chromosome 7. Moreover, a recent GWAS of the addiction explained that some genes, which were identified as risk factors of smoking, show an unbalanced expression of alleles biased towards paternal alleles, which may be caused by paternally derived effect ( Kozlova et al, 2021 ). On the other hand, more and more studies have claimed that some genes with imprinting effects have a significant impact on psychiatric disorders, such as schizophrenia and bipolar disorder.…”