One of the key features of addiction is the escalated drug intake. The neural mechanisms involved in the transition to addiction remain to be elucidated. Since abnormal neuronal activity within the subthalamic nucleus (STN) stands as potential general neuromarker common to impulse control spectrum deficits, as observed in obsessive–compulsive disorders, the present study recorded and manipulated STN neuronal activity during the initial transition to addiction (i.e., escalation) and post-abstinence relapse (i.e., re-escalation) in rats with extended drug access. We found that low-frequency (theta and beta bands) neuronal oscillations in the STN increase with escalation of cocaine intake and that either lesion or high-frequency stimulation prevents the escalation of cocaine intake. STN–HFS also reduces re-escalation after prolonged, but not short, protracted abstinence, suggesting that STN–HFS is an effective prevention for relapse when baseline rates of self-administration have been re-established. Thus, STN dysfunctions may represent an underlying mechanism for cocaine addiction and therefore a promising target for the treatment of addiction.
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Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, Lazzaro VD. Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson’s disease. J Neurosci. 2001;21:1033–8.
Limousin P, Pollak P, Benazzouz A, Hoffmann D, Broussolle E, Perret JE, et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995;345:91–95.
Eusebio A, Cagnan H, Brown P. Does suppression of oscillatory synchronisation mediate some of the therapeutic effects of DBS in patients with Parkinson’s disease? Front Integr Neurosci. 2012;6:47.
Baunez C, Lardeux S. Frontal cortex-like functions of the subthalamic nucleus. Front Syst Neurosci. 2011;5.
Eagle DM, Baunez C. Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition. Neurosci Biobehav Rev. 2010;34:50–72.
Welter M-L, Burbaud P, Fernandez-Vidal S, Bardinet E, Coste J, Piallat B, et al. Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy. Transl Psychiatry. 2011;1:e5.
Darbaky Y, Baunez C, Arecchi P, Legallet E, Apicella P. Reward-related neuronal activity in the subthalamic nucleus of the monkey. Neuroreport. 2005;16:1241–4.
Lardeux S, Pernaud R, Paleressompoulle D, Baunez C. Beyond the reward pathway: coding reward magnitude and error in the rat subthalamic nucleus. J Neurophysiol. 2009;102:2526–37.
Lardeux S, Paleressompoulle D, Pernaud R, Cador M, Baunez C. Different populations of subthalamic neurons encode cocaine vs. sucrose reward and predict future error. J Neurophysiol. 2013;110:1497–510.
Breysse E, Pelloux Y, Baunez C. The good and bad differentially encoded within the subthalamic nucleus in rats. eNeuro. 2015;2:e0014–15.
Zénon A, Duclos Y, Carron R, Witjas T, Baunez C, Régis J, et al. The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making. Brain J Neurol. 2016;139:1830–43.
Ahmed SH, Koob GF. Transition from moderate to excessive drug intake: change in hedonic set point. Science. 1998;282:298–300.
Ahmed SH. The science of making drug-addicted animals. Neuroscience. 2012;211:107–25.
Baunez C, Dias C, Cador M, Amalric M. The subthalamic nucleus exerts opposite control on cocaine and ‘natural’ rewards. Nat Neurosci. 2005;8:484–9.
Rouaud T, Lardeux S, Panayotis N, Paleressompoulle D, Cador M, Baunez C. Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. Proc Natl Acad Sci USA. 2010;107:1196–1200.
Pelloux Y, Baunez C. Deep brain stimulation for addiction: why the subthalamic nucleus should be favored. Curr Opin Neurobiol. 2013;23:713–20.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 2013. 7th edn. Academic Press, Cambridge.
Darbaky Y, Forni C, Amalric M, Baunez C. High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task. Eur J Neurosci. 2003;18:951–6.
Guillem K, Ahmed SH, Peoples LL. Escalation of cocaine intake and incubation of cocaine seeking are correlated with dissociable neuronal processes in different accumbens subregions. Biol Psychiatry. 2014;76:31–9.
Wade CL, Kallupi M, Hernandez DO, Breysse E, de Guglielmo G, Crawford E, et al. High-frequency stimulation of the subthalamic nucleus blocks compulsive-like re-escalation of heroin taking in rats. Neuropsychopharmacol. 2017;42:1850–9.
Roth ME, Carroll ME. Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav. 2004;78:199–207.
Wee S, Mandyam CD, Lekic DM, Koob GF. Alpha 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access. Eur Neuropsychopharmacol. 2008;18:303–11.
Mantsch JR, Yuferov V, Mathieu-Kia A-M, Ho A, Kreek MJ. Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology. 2004;175:26–36.
Vanderschuren LJMJ, Everitt BJ. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science. 2004;305:1017–9.
Meissner W, Leblois A, Hansel D, Bioulac B, Gross CE, Benazzouz A, et al. Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations. Brain. 2005;128:2372–82.
Mallet N, Pogosyan A, Sharott A, Csicsvari J, Bolam JP, Brown P, et al. Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. J Neurosci 2008;28:4795–806.
Ahmed SH, Kenny PJ, Koob GF, Markou A. Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci. 2002;5:625–6.
Alcaro A, Panksepp J. The SEEKING mind: primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression. Neurosci Biobehav Rev. 2011;35:1805–20.
Magill PJ, Bolam JP, Bevan MD. Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience. 2001;106:313–30.
Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson’s disease. Brain J Neurol. 2002;125:1196–209.
Hamani C, Florence G, Heinsen H, Plantinga BR, Temel Y, Uludag K, et al. Subthalamic nucleus deep brain stimulation: basic concepts and novel perspectives. eNeuro. 2017;4:140–17.
Deffains M, Iskhakova L, Katabi S, Haber SN, Israel Z, Bergman H. Subthalamic, not striatal, activity correlates with basal ganglia downstream activity in normal and parkinsonian monkeys. eLife. 2016;5:e16443.
Bergman H, Wichmann T, Karmon B, DeLong MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol. 1994;72:507–20.
Degos B, Deniau J-M, Thierry A-M, Glowinski J, Pezard L, Maurice N. Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus. J Neurosci. 2005;25:7687–96.
Delaville C, McCoy AJ, Gerber CM, Cruz AV, Walters JR. Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks. J Neurosci. 2015;35:6918–30.
Huebl J, Spitzer B, Brücke C, Schönecker T, Kupsch A, Alesch F, et al. Oscillatory subthalamic nucleus activity is modulated by dopamine during emotional processing in Parkinson’s disease. Cortex. 2014;60:69–81.
Pelloux Y, Meffre J, Giorla E, Baunez C. The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation. Front Behav Neurosci. 2014;8:414.
Priori A, Foffani G, Pesenti A, Tamma F, Bianchi AM, Pellegrini M, et al. Rhythm-specific pharmacological modulation of subthalamic activity in Parkinson’s disease. Exp Neurol. 2004;189:369–79.
Baunez C, Nieoullon A, Amalric M. In a rat model of parkinsonism, lesions of the subthalamic nucleus reverse increases of reaction time but induce a dramatic premature responding deficit. J Neurosci. 1995;15:6531–41.
Baunez C, Robbins TW. Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats. Eur J Neurosci. 1997;9:2086–99.
Baunez C, Humby T, Eagle DM, Ryan LJ, Dunnett SB, Robbins TW. Effects of STN lesions on simple vs choice reaction time tasks in the rat: preserved motor readiness, but impaired response selection. Eur J Neurosci. 2001;13:1609–16.
Adams WK, Vonder Haar C, Tremblay M, Cocker PJ, Silveira MM, Kaur S, et al. Deep-brain stimulation of the subthalamic nucleus selectively decreases risky choice in risk-preferring rats. eNeuro. 2017;4:e94–17.
Mallet L, Polosan M, Jaafari N, Baup N, Welter M-L, Fontaine D, et al. Subthalamic nucleus stimulation in severe obsessive–compulsive disorder. N Engl J Med. 2008;359:2121–34.
de Hemptinne C, Swann NC, Ostrem JL, Ryapolova-Webb ES, San Luciano M, Galifianakis NB, et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson’s disease. Nat Neurosci. 2015;18:779–86.
Hachem-Delaunay S, Fournier M-L, Cohen C, Bonneau N, Cador M, Baunez C, et al. Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit. Neurobiol Dis. 2015;80:54–62.
Paul Krack, Marwan I. Hariz, Christelle Baunez, Jorge Guridi, Jose A. Obeso. Deep brain stimulation: from neurology to psychiatry? Trends in Neurosciences. 2010;33:474–84.
Luigjes J, van den Brink W, Feenstra M, van den Munckhof P, Schuurman PR, Schippers R, et al. Deep brain stimulation in addiction: a review of potential brain targets. Mol Psychiatry. 2012;17:572–83.
Vassoler FM, Schmidt HD, Gerard ME, Famous KR, Ciraulo DA, Kornetsky C, et al. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. J Neurosci. 2008;28:8735–9.
Creed M, Pascoli VJ, Lüscher C. Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science. 2015;347:659–64.
Eusebio A, Witjas T, Cohen J, Fluchère F, Jouve E, Régis J, et al. Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2013;84:868–74.
The authors thank Drs. P Carrieri, C Bernard, P Belin, F Brocard, and G Masson for critical reading of the manuscript and the technical support from J. Baurberg and animal facilities personal. This research was funded by CNRS, Aix-Marseille Université (AMU), the “Agence Nationale pour la Recherche” (ANR_2010-NEUR-005-01 in the framework of the ERA-Net NEURON to CB and supporting to YP), the Fondation pour la Recherche Médicale (FRM DPA20140629789 to CB), National Institutes of Health grants DA (DA029821 to GFK) from the National Institute on Drug Abuse and the Fondation de l’Avenir (ET2-655 to CB).
Conflict of interest
The authors declare that they have no conflict of interest.
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Pelloux, Y., Degoulet, M., Tiran-Cappello, A. et al. Subthalamic nucleus high frequency stimulation prevents and reverses escalated cocaine use. Mol Psychiatry 23, 2266–2276 (2018). https://doi.org/10.1038/s41380-018-0080-y
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