Abstract
Opioid addiction, including addiction to heroin, has markedly increased in the past decade. The cost and pervasiveness of heroin addiction, including resistance to recovery from addiction, provide a compelling basis for developing novel therapeutic strategies. Deep brain stimulation may represent a viable alternative strategy for the treatment of intractable heroin addiction, particularly in individuals who are resistant to traditional therapies. Here we provide preclinical evidence of the therapeutic potential of high-frequency stimulation of the subthalamic nucleus (STN HFS) for heroin addiction. STN HFS prevented the re-escalation of heroin intake after abstinence in rats with extended access to heroin, an animal model of compulsive heroin taking. STN HFS inhibited key brain regions, including the substantia nigra, entopeduncular nucleus, and nucleus accumbens shell measured using brain mapping analyses of immediate-early gene expression and produced a robust silencing of STN neurons as measured using whole-cell recording ex vivo. These results warrant further investigation to examine the therapeutic effects that STN HFS may have on relapse in humans with heroin addiction.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki V, Hosseini H et al (2006). Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation. Movement Disord 21: 1941–1946.
Barbier E, Vendruscolo LF, Schlosburg JE, Edwards S, Juergens N, Park PE et al (2013). The NK1 receptor antagonist L822429 reduces heroin reinforcement. Neuropsychopharmacology 38: 976–984.
Baunez C, Dias C, Cador M, Amalric M (2005). The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewards. Nat Neurosci 8: 484–489.
Benazzouz A, Piallat B, Pollak P, Benabid AL (1995). Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data. Neurosci Lett 189: 77–80.
Beurrier C, Bioulac B, Audin J, Hammond C (2001). High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 85: 1351–1356.
Chen SA, O'Dell LE, Hoefer ME, Greenwell TN, Zorrilla EP, Koob GF (2006). Unlimited access to heroin self-administration: independent motivational markers of opiate dependence. Neuropsychopharmacology 31: 2692–2707.
Crane EH (2015) The CBHSQ Report: Emergency Department Visits Involving Narcotic Pain Relievers. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality: Rockville, MD.
Creed MC, Hamani C, Nobrega JN (2012). Early gene mapping after deep brain stimulation in a rat model of tardive dyskinesia: comparison with transient local inactivation. Eur Neuropsychopharmacol 22: 506–517.
Darbaky Y, Forni C, Amalric M, Baunez C (2003). 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 18: 951–956.
Filali M, Hutchison WD, Palter VN, Lozano AM, Dostrovsky JO (2004). Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus. Exp Brain Res 156: 274–281.
Garcia L, Audin J, D'Alessandro G, Bioulac B, Hammond C (2003). Dual effect of high-frequency stimulation on subthalamic neuron activity. J Neurosci 23: 8743–8751.
Geday J, Ostergaard K, Gjedde A (2006). Stimulation of subthalamic nucleus inhibits emotional activation of fusiform gyrus. NeuroImage 33: 706–714.
Guercio LA, Schmidt HD, Pierce RC (2015). Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats. Behav Brain Res 281: 125–130.
Guo L, Zhou H, Wang R, Xu J, Zhou W, Zhang F et al (2013). DBS of nucleus accumbens on heroin seeking behaviors in self-administering rats. Drug Alcohol Depend 129: 70–81.
Hachem-Delaunay S, Fournier ML, Cohen C, Bonneau N, Cador M, Baunez C et al (2015). Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit. Neurobiol Dis 80: 54–62.
Hamani C, Pilitis J, Rughani A, Rosenow J, Patil P, Slavin K et al (2014). Deep brain stimulation for obsessive-compulsive disorder: systematic review and evidence-based guideline sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (CNS) and endorsed by the CNS and American Association of Neurological Surgeons. Neurosurgery 74: 327–333.
Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL (2003). Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci 23: 1916–1923.
Henderson JM, Dunnett SB (1998). Targeting the subthalamic nucleus in the treatment of Parkinson's disease. Brain Res Bull 46: 467–474.
Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF (2006). Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J Neurosci 26: 5894–5900.
Kuhn J, Moller M, Treppmann JF, Bartsch C, Lenartz D, Gruendler TO et al (2014). Deep brain stimulation of the nucleus accumbens and its usefulness in severe opioid addiction. Mol Psychiatry 19: 145–146.
Le Jeune F, Peron J, Grandjean D, Drapier S, Haegelen C, Garin E et al (2010a). Subthalamic nucleus stimulation affects limbic and associative circuits: a PET study. Eur J Nucl Med Mol Imag 37: 1512–1520.
Le Jeune F, Verin M, N'Diaye K, Drapier D, Leray E, Du Montcel ST et al (2010b). Decrease of prefrontal metabolism after subthalamic stimulation in obsessive-compulsive disorder: a positron emission tomography study. Biol Psychiatry 68: 1016–1022.
Lee KH, Roberts DW, Kim U (2003). Effect of high-frequency stimulation of the subthalamic nucleus on subthalamic neurons: an intracellular study. Stereotactic Funct Neurosurg 80: 32–36.
Magarinos-Ascone C, Pazo JH, Macadar O, Buno W (2002). High-frequency stimulation of the subthalamic nucleus silences subthalamic neurons: a possible cellular mechanism in Parkinson's disease. Neuroscience 115: 1109–1117.
Mallet L, Mesnage V, Houeto JL, Pelissolo A, Yelnik J, Behar C et al (2002). Compulsions, Parkinson's disease, and stimulation. Lancet 360: 1302–1304.
Mallet L, Polosan M, Jaafari N, Baup N, Welter ML, Fontaine D et al (2008). Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med 359: 2121–2134.
McLellan AT, Lewis DC, O'Brien CP, Kleber HD (2000). Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284: 1689–1695.
Paxinos G, Watson C, Pennisi M, Topple A (1985). Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 13: 139–143.
Pelloux Y, Meffre J, Giorla E, Baunez C (2014). The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation. Front Behav Neurosci 8: 414.
Pollak P, Fraix V, Krack P, Moro E, Mendes A, Chabardes S et al (2002). Treatment results: Parkinson's disease. Movement Disord 17 (Suppl 3): S75–S83.
Rouaud T, Lardeux S, Panayotis N, Paleressompoulle D, Cador M, Baunez C (2010). Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. Proc Natl Acad Sci USA 107: 1196–1200.
Schlosburg JE, Vendruscolo LF, Bremer PT, Lockner JW, Wade CL, Nunes AA et al (2013). Dynamic vaccine blocks relapse to compulsive intake of heroin. Proc Natl Acad Sci USA 110: 9036–9041.
Shehab S, D'Souza C, Ljubisavljevic M, Redgrave P (2014). High-frequency electrical stimulation of the subthalamic nucleus excites target structures in a model using c-fos immunohistochemistry. Neuroscience 270: 212–225.
Smyth B, Hoffman V, Fan J, Hser YI (2007). Years of potential life lost among heroin addicts 33 years after treatment. Prev Med 44: 369–374.
Stephen JH, Halpern CH, Barrios CJ, Balmuri U, Pisapia JM, Wolf JA et al (2012). Deep brain stimulation compared with methadone maintenance for the treatment of heroin dependence: a threshold and cost-effectiveness analysis. Addiction 107: 624–634.
Tai CH, Boraud T, Bezard E, Bioulac B, Gross C, Benazzouz A (2003). Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J 17: 1820–1830.
Tan SK, Janssen ML, Jahanshahi A, Chouliaras L, Visser-Vandewalle V, Lim LW et al (2011). High frequency stimulation of the subthalamic nucleus increases c-fos immunoreactivity in the dorsal raphe nucleus and afferent brain regions. J Psychiatric Res 45: 1307–1315.
Valencia-Alfonso CE, Luigjes J, Smolders R, Cohen MX, Levar N, Mazaheri A et al (2012). Effective deep brain stimulation in heroin addiction: a case report with complementary intracranial electroencephalogram. Biol Psychiatry 71: e35–e37.
Vassoler FM, Schmidt HD, Gerard ME, Famous KR, Ciraulo DA, Kornetsky C et al (2008). Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. J Neurosci 28: 8735–8739.
Vassoler FM, White SL, Hopkins TJ, Guercio LA, Espallergues J, Berton O et al (2013). Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation. J Neurosci 33: 14446–14454.
Vendruscolo LF, Schlosburg JE, Misra KK, Chen SA, Greenwell TN, Koob GF (2011). Escalation patterns of varying periods of heroin access. Pharmacol Biochem Behav 98: 570–574.
Winter C, Lemke C, Sohr R, Meissner W, Harnack D, Juckel G et al (2008). High frequency stimulation of the subthalamic nucleus modulates neurotransmission in limbic brain regions of the rat. Exp Brain Res 185: 497–507.
Witjas T, Baunez C, Henry JM, Delfini M, Regis J, Cherif AA et al (2005). Addiction in Parkinson's disease: impact of subthalamic nucleus deep brain stimulation. Movement Disord 20: 1052–1055.
Zhou H, Xu J, Jiang J (2011). Deep brain stimulation of nucleus accumbens on heroin-seeking behaviors: a case report. Biol Psychiatry 69: e41–e42.
Acknowledgements
We thank Michael Arends for proofreading the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Wade, C., Kallupi, M., Hernandez, D. et al. High-Frequency Stimulation of the Subthalamic Nucleus Blocks Compulsive-Like Re-Escalation of Heroin Taking in Rats. Neuropsychopharmacol 42, 1850–1859 (2017). https://doi.org/10.1038/npp.2016.270
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2016.270
This article is cited by
-
Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice
Psychopharmacology (2025)
-
Subthalamic high-frequency deep brain stimulation reduces addiction-like alcohol use and the possible negative influence of a peer presence
Psychopharmacology (2025)
-
Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats
Behavioral and Brain Functions (2023)
-
Are we compulsively chasing rainbows?
Neuropsychopharmacology (2022)
-
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?
Neurotherapeutics (2022)