Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats

Neuropharmacology. 2012 Jan;62(1):167-76. doi: 10.1016/j.neuropharm.2011.06.014. Epub 2011 Jun 29.


Drug dependence is characterized by dysregulation of brain reward systems and increased sensitivity to stress. Chronic exposure to drugs of abuse is associated with increased expression of the neuropeptide dynorphin, the endogenous ligand for kappa opioid receptors (KORs). Activation of KORs causes depressive- and aversive-like responses in rodents, raising the possibility that drug-induced upregulation of dynorphin plays a role independence-associated negative states. Here we used "binge" exposure to cocaine (3 daily intraperitoneal injections of 15 mg/kg for 14 days) to examine the development of dependence-like behavior in the intracranial self-stimulation (ICSS) test and the forced swim test (FST). When rats were tested 1 h before their first scheduled injection of each day-a period of drug withdrawal corresponding to 20 h after their last injection on the previous day-there were exposure-dependent increases in ICSS thresholds (a putative indicator of anhedonia) and decreases in latencies to immobility in the FST (a putative indicator of behavioral despair). Administration of the long-lasting KOR antagonist norBNI (20 μg, intracerebroventricular) before the beginning of the binge regimen attenuated the development of cocaine withdrawal-induced anhedonia in the ICSS test. In contrast, administration of norBNI in the midst of the binge regimen had no effect on expression of cocaine withdrawal-induced anhedonia in the ICSS test, although it did attenuate despair-like behavior in the FST. These data suggest that blockade of KORs before exposure to a stressor (in this case, cocaine withdrawal or forced swimming) can attenuate the development of stress-induced behavioral adaptations. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Cocaine / adverse effects
  • Conditioning, Operant / drug effects
  • Depression / drug therapy
  • Depression / etiology*
  • Depression / metabolism*
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / adverse effects
  • Drug Administration Routes
  • Immobility Response, Tonic / drug effects
  • Male
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Receptors, Opioid, kappa / antagonists & inhibitors
  • Receptors, Opioid, kappa / metabolism*
  • Reinforcement Schedule
  • Self Administration
  • Substance Withdrawal Syndrome / complications*
  • Swimming / psychology
  • Time Factors


  • Dopamine Uptake Inhibitors
  • Narcotic Antagonists
  • Receptors, Opioid, kappa
  • norbinaltorphimine
  • Naltrexone
  • Cocaine