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

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 (LTP_GABA). Our studies have shown that exposure to acute stress blocks this LTP and that reversal of the block of LTP_GABA 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 selfadministration was tested. Results: We found that an acute stressor blocks LTP_GABA 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 LTP_GABA. 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.