Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction

Abstract

Significance Understanding why some individuals become addicts while others can maintain recreational use, and how to treat these individuals, remains a challenge. Using a state-of-the-art rat model of compulsive cocaine seeking (resistance to a punishment associated with cocaine seeking), we show here that: first, subthalamic nucleus (STN) oscillatory activity during prior extended access to cocaine serves as a biomarker to predict vulnerable individuals that will compulsively seek the drug, a hallmark of addiction, and second, that in compulsive “addicted” rats, low (30 Hz) but not high (130 Hz), deep brain stimulation (DBS) of the STN efficiently reduces pathological cocaine seeking. Given that DBS approaches are currently used for neurologic and psychiatric disorders in human patients, our results provide highly translational observations. Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.