Addiction-Related Transcription Changes in the Brain
Mounting evidence indicates that drug addiction leads to long-term adaptations within the brain’s reward circuitry. One outcome of this is that exposure to the drug or drug-associated cues can trigger a relapse of addiction even after a long period of abstinence. Research has begun to outline changes in signaling cascades and correlated transcriptional responses associated with addiction and withdrawal, but no studies have attempted to outline these changes on a global basis across multiple brain regions. This led Vanderbilt Basic Sciences investigator Erin Calipari and her colleagues Li Shen and Eric Nestler (Icahn School of Medicine at Mount Sinai) to examine transcriptional changes associated with cocaine withdrawal and re-exposure across six reward-related brain regions in rats. They first trained the rats to self-administer (SA) either saline or cocaine, and then performed RNA-seq analysis on the six brain regions either after a 24 h withdrawal period or a 30 day withdrawal period followed by administration of saline or cocaine in the presence of a cocaine-associated cue. Extensive analysis of the resulting vast dataset revealed some key new insights. First, they identified three unique patterns of gene expression changes that were associated with acute first exposure to cocaine, exposure to a cocaine-associated cue following withdrawal, or exposure to cocaine and the cocaine-associated cue following withdrawal. In each case, some of the gene expression changes associated with each pattern occurred across multiple brain regions, and the investigators were able to identify likely upstream regulators that modulated each of the changes. Of particular importance was CREB1, identified as a likely modulator of all three patterns of expression. Analysis of the behavior of the rats defined three factors associated with addiction: the amount of cocaine SA, the ability to distinguish between levers that do or do not provide the drug, and the ability to increase SA frequency to compensate for decreased drug dose per lever press. They combined these factors to calculate an addiction index (AI) for each rat and then identified gene transcription changes associated with the AI. Some of the AI-related genes, such as that encoding lipocalin 2 (Lcn2), were associated with addiction behavior across multiple brain regions, suggesting that they might be viable therapeutic targets. Further analysis demonstrated the importance of nuclear receptors in the differential modulation of gene expression across the various brain regions. This led the investigators to postulate that nuclear receptors are responsible for fine-tuning responses to transcription factors such as CREB1 that appear to play a global role in the response to addiction and withdrawal. The data supports the hypothesis that addiction primes the reward center to respond to drug or drug-associated context exposure in a way that reinforces addiction. Information gleaned from these data will point the way to new approaches to understand and treat addiction and/or prevent relapse. The work is published in Biological Psychiatry [D. M. Walker, H. M. Coates, Y-H. E. Loh, et al. (2018) Biol. Psych., Published online April 17, doi: 10.1016/j.biopsych.2018.04.009.]