Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking

Biol Psychiatry. 2014 Nov 15;76(10):785-93. doi: 10.1016/j.biopsych.2014.04.019. Epub 2014 May 21.


Background: Dopaminergic neurons in the ventral tegmental area of the brain are an important site of convergence of drugs and stress. We previously identified a form of long-term potentiation of gamma-aminobutyric acid (GABA)ergic synapses on these neurons (LTPGABA). Our studies have shown that exposure to acute stress blocks this LTP and that reversal of the block of LTPGABA is correlated with prevention of stress-induced reinstatement of cocaine-seeking behavior.

Methods: Sprague-Dawley rats were subjected to cold-water swim stress. Midbrain slices were prepared following stress, and whole-cell patch clamp recordings of inhibitory postsynaptic currents were performed from ventral tegmental area dopamine neurons. Antagonists of glucocorticoid receptors and kappa opioid receptors (κORs) were administered at varying time points after stress. Additionally, the ability of a kappa antagonist administered following stress to block forced swim stress-induced reinstatement of cocaine self-administration was tested.

Results: We found that an acute stressor blocks LTPGABA for 5 days after stress through a transient activation of glucocorticoid receptors and more lasting contribution of κORs. Even pharmacological block of κORs beginning 4 days after stress has occurred reversed the block of LTPGABA. Administration of a κORs antagonist following stress prevents reinstatement of cocaine-seeking behavior.

Conclusions: A brief stressor produces changes in the reward circuitry lasting several days. Our findings reveal roles for glucocorticoid receptors and κORs as mediators of the lasting effects of stress on synaptic plasticity. κORs antagonists reverse the neuroadaptations underlying stress-induced drug-seeking behavior and may be useful in the treatment of cocaine addiction.

Keywords: Glucocorticoid receptor; kappa opioid receptor; reinstatement; stress; synaptic plasticity; ventral tegmental area.

Publication types

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

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Corticosterone / blood
  • Dexamethasone / pharmacology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / physiology
  • Drug-Seeking Behavior / physiology*
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / physiology
  • Glucocorticoids / pharmacology
  • Inhibitory Postsynaptic Potentials*
  • Long-Term Potentiation*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Opioid, kappa / physiology*
  • Self Administration
  • Stress, Psychological / physiopathology*
  • Swimming
  • Tegmentum Mesencephali / drug effects
  • Tegmentum Mesencephali / physiology


  • Glucocorticoids
  • Receptors, Glucocorticoid
  • Receptors, Opioid, kappa
  • Dexamethasone
  • Cocaine
  • Corticosterone