Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence

PROJECT SUMMARY Relapse prevention is a major goal in the treatment of alcohol use disorder (alcoholism), as many alcoholics return to alcohol use even after a prolonged period of successful abstinence. The chronically relapsing nature of alcoholism is thought to be exacerbated by the intensification of alcohol craving during abstinence. However, the brain mechanisms causing this intensification process remains unknown. Like alcohol craving provoked by environmental stimuli signaling alcohol (‘alcohol cues’) in recovering alcoholics, cue-provoked alcohol seeking in rats is known to intensify during abstinence. We have found that alcohol ‘cue-reactive’ neurons (expressing the activation marker Fos) in the nucleus accumbens (NAc) core drive this behavioral intensification, thereby identifying these neurons as neural targets functionally linked to cue-provoked alcohol seeking. We also found that these ‘cue-reactive’ neurons undergo unique transcriptional adaptations during abstinence (including those linked to alcoholism/drug addiction) that are largely distinct from adaptations in adjacent ‘non-reactive’ neurons. While these results provide gene targets specific to behaviorally functional neural units, we have so far identified such adaptations (across relatively short abstinence) in rats that were well-trained to self-administer alcohol but were not subjected to physical dependence-inducing procedures. These ‘non-dependent’ rats will thus likely model ‘casual drinkers’ but perhaps not patients with alcoholism. Indeed, alcoholics are known to report greater cue-provoked craving than non-dependent drinkers and show different patterns of neural cue- reactivities. Similarly, cue-provoked alcohol seeking in rats with or without a history of physical dependence is known to be controlled by different brain mechanisms. However, no study has yet characterized abstinence- induced intensification of alcohol seeking in animals with dependence histories. We thus next used chronic intermittent alcohol vapor exposures to induce physical dependence and found that rats with histories of dependence show greater cue-provoked alcohol seeking and greater intensification of this behavior than non- dependent rats during prolonged abstinence. These ‘dependent’ rats will thus likely better model the intensification of alcohol craving in recovering alcoholics than ‘non-dependent’ rats, thereby providing more relevant mechanical insights into the chronically relapsing nature of alcoholism. Based on the premise above, this R21 project will test the central hypothesis that “transcriptional adaptations unique to alcohol cue-reactive neurons in NAc core drive the intensification of cue-provoked alcohol seeking in alcohol dependent rats undergoing prolonged abstinence”. We will use neural activity-specific transcriptional profiling (Aim 1) and gene rescuing (Aim 2) to selectively target alcohol ‘cue-reactive’ – rather than ‘non-reactive’ – neurons. The results will determine which transcriptional adaptations are functionally linked to the intensification of alcohol seeking in dependent rats undergoing prolonged abstinence. Such knowledge may help identify novel therapeutic targets for developing anti-relapse medication to counter intensifying alcohol craving in recovering alcoholics.