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Reversing compulsive cocaine seeking with low frequency deep brain stimulation of the subthalamic nucleus

Addictive individuals continue to seek and take drugs of abuse despite obvious negative consequences for their personal, professional and social life.1 Although significant advances have been made in our understanding of brain mechanisms leading to compulsive drug seeking/taking, there is still no FDA-approved pharmacological treatment for cocaine addiction. Resurgence of surgical techniques such as deep brain stimulation (DBS) for the treatment of neurodegenerative and psychiatric diseases, including Parkinson’s disease (PD), obsessive compulsive disorders (OCD) and depression,2-4 has recently opened new therapeutic perspectives for the treatment of addictive disorders. Although the ideal brain target is still a matter of debate,5-7 the subthalamic nucleus (STN) stands as a solid candidate since its 130 Hz DBS reduces drug-induced addiction-like behaviors.8-10 Here we used a rat model of compulsive cocaine seeking11,12 in which, after extended cocaine taking history, a subset of rats compulsively seek cocaine despite intermittent punishment by mild electric foot shock. We show that this pathological behavior is predicted by an abnormal increase in STN low frequency oscillations power, especially in the theta band (6-12 Hz), during prolonged cocaine consumption. Conversely, very low frequency (8 Hz) stimulation of the STN of ‘shock-sensitive’ rats during extended cocaine access triggers compulsive drug seeking upon subsequent re-exposure to the punishment, demonstrating that abnormal very low frequency oscillatory activity within the STN is causally involved in the emergence of compulsive cocaine seeking and represents a predictive marker of pathological drug seeking. Finally, we also demonstrate that 30 Hz, but not 130 Hz, STN DBS has a beneficial effect at reducing compulsive cocaine seeking in ‘shock-resistant’ animals. By evidencing a frequency-dependent bidirectional control of STN DBS on compulsive cocaine seeking, our results outline the critical contribution of the STN to the onset and maintenance of pathological cocaine seeking behaviors and further emphasize the therapeutic potential of STN DBS for the treatment of addiction.