MicroRNA cluster miR199a/214 are differentially expressed in female and male rats following nicotine self-administration

Abstract

Previous research has established sex differences associated with nicotine intake, however a significant gap in knowledge remains regarding the molecular mechanisms that govern these differences at the transcriptional level. One critical regulator of transcription are microRNAs (miRNAs). miRNAs are a family of non-coding RNAs that regulate an array of important biological functions altered in several disease states, including neuroadaptive changes within the brain associated with drug dependence. We examined the prefrontal cortex (PFC) from male and female Sprague-Dawley rats following self-administration (22 days) of nicotine or yoked saline controls using next generation RNA-Sequencing (RNA-Seq) technology and found an array of miRNAs to be significantly and differentially regulated by nicotine self-administration. Of these, we found the expression of miR-199a and 214, which are expressed on the same cluster of chromosome 1, to be upregulated in the female rats exposed to nicotine; upregulation in this group was further validated by real time polymerase chain reaction (RT-PCR). Bioinformatics analysis to assess common targets of miR-199/214 identified Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)- dependent deacetylase that plays a role in apoptosis, neuron survival, and stress resistance. Using western-blot, we confirmed downregulation of SIRT1 and increased cleaved caspase 3 expression in the brains of nicotine-exposed female rats and no change in expression levels in the other groups. Collectively, our findings highlight a miR-199/214 regulatory network that, through SIRT1, may be associated with nicotine seeking in females which may serve as a potential therapeutic target for sex-specific treatment approaches.

Role of Brain Derived Extracellular Vesicles in Decoding Sex Differences Associated with Nicotine Self-Administration

“…Our previously published study revealed that male and female rats readily self-administered nicotine, while yoked saline maintained very little responding [29]. In addition, we also reported that female rats had a significantly higher total nicotine intake than males, which is consistent with previously published papers [11,14,15,[35][36][37].…”

“…Our previously published study demonstrated the impact of nicotine on sex differences through a drug self-administration model that mimics human drug-taking behavior [29]. Though male and female rats readily self-administer nicotine, female rats had a significantly higher total nicotine intake than males (+1.35 fold).…”

“…The brain tissue used in this study was from a previously published work from our group [29]. Briefly, 9-week-old male and female Sprague Dawley rats were trained for lever presses following which rats were surgically implanted with a jugular catheter (IUCAC #1477 and Animal Welfare Assurance Number A3459-01).…”

Male HIV‐1 transgenic rats show reduced cocaine‐maintained lever‐pressing compared to F344 wildtype rats despite similar baseline locomotion

“…All rats underwent jugular catheter surgery using our established protocol (Charntikov et al, ; Pittenger et al, ). Rats were anaesthetized with a 1 ml/kg intramuscular injection of a ketamine hydrochloride (100 mg/mL): xylazine hydrochloride (20 mg/mL) cocktail (Midwestern Veterinary Supply, Des Moines, IA, USA).…”

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

“…Previous transcriptomic studies of NIC SA in rodents often use strains with different genetic backgrounds that may confound the results 35,36 , or have an experimental setting that assay the acute effect of NIC exposure rather than the molecular changes that may lead to SA 37 .…”