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.

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A complex interplay of peripheral and central signaling mechanisms within the body of an organism maintains energy homeostasis. In addition, energy/food intake is modified by various external factors (e.g., palatability, food availability, social and environmental triggers). Highly palatable foods can provoke maladaptive feeding behavior, which in turn disrupts normal homeostatic regulation resulting in numerous health consequences. Furthermore, neuroendocrine peptides, traditionally considered to regulate appetite and energy homeostasis, also control the intake and reinforcing properties of alcohol and drugs of abuse. Therefore, dysregulated eating as a result of a hedonic/binge-like intake of hyper-palatable food may impact alcohol drinking behavior. Relevant in this case is the fact that eating disorders are highly comorbid with several neuropsychiatric conditions, including alcohol use disorder. The present review is intended to summarize the neurobiological and functional consequences of hedonic feeding on alcohol intake.