Abstract
It is well established that cannabis use promotes appetite. However, how cannabis interacts with the brain’s appetite center, the hypothalamus, to stimulate feeding behavior is unknown. A growing body of evidence indicates that the hypothalamic transcriptome programs energy balance. Here, we tested the hypothesis that cannabis targets alternative polyadenylation (APA) sites within hypothalamic transcripts to regulate transcriptomic function. To do this, we used a novel cannabis vapor exposure model to characterize feeding in adult male Long Evans rats and aligned this behavioral response with APA events using a Whole Transcriptome Termini Sequencing (WTTS-Seq) approach as well as functional RNA abundance measurements with real-time quantitative polymerase chain reactions. We found that vapor cannabis exposure promoted food intake in free-feeding and behaviorally sated rats, validating the appetite stimulating properties of cannabis. Our WTTS-Seq analysis mapped 59 unique cannabis-induced hypothalamic APAs that occurred primarily within exons on transcripts that regulate synaptic function, excitatory synaptic transmission, and dopamine signaling. Importantly, APA insertions regulated RNA abundance of Slc6a3, the dopamine transporter, suggesting a novel genetic link for cannabis regulation of brain monoamine function. Collectively, these novel data indicate that a single cannabis exposure rapidly targets a key RNA processing mechanism linked to brain transcriptome function.
Highlights
Cannabis is the most widely used illicit substance worldwide[1] and its recent legalization has brought into question both its therapeutic potential and abuse liability[2,3,4,5,6]
We observed that cannabis exposure significantly increased chow intake in free-feeding rats
Our data indicate that cannabis can promote feeding in the presence or absence of a caloric need, a phenomenon that occurred over a short duration of time following a single exposure to cannabis
Summary
Cannabis is the most widely used illicit substance worldwide[1] and its recent legalization has brought into question both its therapeutic potential and abuse liability[2,3,4,5,6]. New evidence indicates that alternative polyadenylation (APA) of mRNAs, an RNA processing mechanism that generates 3′ termini on transcripts, is a key genetic mechanism that regulates mRNA abundance and localization, and as a result, the biological function of neurons[22,24,25] This improved understanding of APA biology has led to its use as a biomarker for behavioral disorders and a measure of effectiveness for pharmacotherapies used to mitigate these conditions[26,27,28,29,30,31]. Biological replication studies indicated that cannabis-induced APA events were functional to alter RNA abundance of Slc6a3, the rat dopamine transporter In combination, these data highlight APA as a genetic mechanism with rapid restructuring properties that contributes to hypothalamic transcriptome function following cannabis exposure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
