A role for a novel natural antisense-BDNF in the maintenance of nicotine-seeking

Brain derived neurotrophic factor (BDNF) is critical for the extinction of drug-seeking. Expression of the Bdnf gene is highly epigenetically regulated, including via interactions with non-coding RNA. Here we investigate whether a long non-coding RNA antisense to Bdnf exon IV is involved in extinction of drug-seeking. Strand-specific RNA sequencing confirmed the presence of a novel long non-coding RNA antisense to exon IV of the Bdnf gene in the ventromedial prefrontal cortex of adult male rats (Bdnf-IV-AS). Bdnf-IV-AS expression was validated using strand-specific reverse transcription and quantitative polymerase chain reaction following acquisition, extinction or abstinence from intravenous nicotine self-administration. Expression of Bdnf-IV-AS was elevated following intravenous nicotine self-administration but not experimenter-administered nicotine. Elevated Bdnf-IV-AS persisted across abstinence and to a greater extent following extinction training, suggesting an interaction between Bdnf-IV-AS, nicotine and extinction learning. A functional role of the Bdnf-IV-AS 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. Knockdown of the Bdnf-IV-AS across cue-extinction, but not abstinence, significantly attenuated nicotine-primed reinstatement of nicotine-seeking. Bdnf-IV-AS 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.