Neurodegeneration of lateral habenula efferent fibers after intermittent cocaine administration: implications for deep brain stimulation

Neuropharmacology. 2013 Dec;75:246-54. doi: 10.1016/j.neuropharm.2013.06.034. Epub 2013 Jul 24.


Deep brain stimulation (DBS) is an emerging technique for effective, non-pharmacological intervention in the course of neurological and neuropsychiatric diseases. Several brain targets have been suggested as suitable for DBS treatment of drug addiction. Previously, we showed that DBS of the lateral habenula (LHb) can reduce cocaine intake, facilitate extinction and attenuate drug-induced relapse in rats trained to self-administrate cocaine. Herein, we demonstrated that cocaine self-administration dose-dependently decreased connectivity between the LHb and midbrain, as shown by neurodegeneration of the main LHb efferent fiber, the fasciculus retroflexus (FR). FR degeneration, in turn, may have caused lack of response to LHb stimulation in rats trained to self-administer high-dose cocaine (1.5 mg/kg; i.v.). Furthermore, we show that the micro-structural changes caused by cocaine can be non-invasively detected using magnetic resonance imaging and diffusion tensor imaging. Detection of cocaine-induced alterations in FR anatomy can aid the selection of potential responders to LHb stimulation for treatment of drug addiction.

Keywords: Cocaine addiction; Deep brain stimulation; Diffusion tensor imaging; Lateral habenula; Magnetic resonance imaging; Neurodegeneration; Retrograde labeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / complications*
  • Cocaine-Related Disorders / etiology
  • Conditioning, Operant / drug effects
  • Deep Brain Stimulation / methods*
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dose-Response Relationship, Drug
  • Drug-Seeking Behavior
  • Efferent Pathways / pathology
  • Extinction, Psychological / drug effects
  • Habenula / physiology*
  • Male
  • Nerve Degeneration / etiology*
  • Nerve Degeneration / pathology
  • Nerve Degeneration / therapy*
  • Nerve Fibers / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration
  • Ventral Tegmental Area / drug effects


  • Dopamine Uptake Inhibitors
  • Cocaine