A natural antisense to brain-derived neurotrophic factor impairs extinction of drug seeking

Abstract

BACKGROUND: Brain derived neurotrophic factor (BDNF) is critical for the extinction of drug-seeking. Expression of the Bdnf gene is highly regulated via interactions with noncoding RNA, which themselves are altered following drug exposure. Here we investigate whether a novel long non-coding RNA antisense to Bdnf prevents extinction of drug-seeking.METHODS: Strand-specific RNA sequencing identified a novel long non-coding RNA antisense to exon IV of the Bdnf gene in the ventromedial prefrontal cortex of 8 adult male rats. We then assessed asBdnf-IV expression using strand-specific reverse transcription and quantitative polymerase chain reaction following acquisition, extinction or abstinence from intravenous nicotine self-administration (N = 116). A functional role of the asBdnf-IV in extinction of nicotine-seeking was established by infusing gapmer oligonucleotides into the infralimbic cortex prior to extinction and testing for the effect of these infusions on reinstatement and reacquisition of nicotine-seeking (N = 36). RESULTS: RNA sequencing identified the presence of a novel long non-coding RNA antisense to exon IV of the Bdnf gene (asBdnf-IV). Expression of asBdnf-IV was elevated following intravenous nicotine self-administration but not experimenter-administered nicotine. Elevated asBdnf-IV persisted across abstinence and to a greater extent following extinction training, suggesting an interaction between abstinence and extinction learning. In support of this, knockdown of the asBdnf-IV across extinction, but not abstinence, significantly attenuated nicotine-primed reinstatement of nicotine-seeking.CONCLUSIONS: asBdnf-IV accumulates in the infralimbic cortex across self-administration training, interferes with the inhibitory learning that underpins extinction of drug-seeking, and predisposes animals to drug relapse.