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

Abigail M. Polter, Rachel A. Bishop, Lisa A. Briand, Nicholas Graziane, R. Christopher Pierce, Julie A. Kauer

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 selfadministration 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.

Original languageEnglish (US)
Pages (from-to)785-793
Number of pages9
JournalBiological Psychiatry
Volume76
Issue number10
DOIs
StatePublished - Jan 1 2014

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kappa Opioid Receptor
Long-Term Potentiation
Glucocorticoid Receptors
Opioid Receptors
Cocaine
Synapses
Ventral Tegmental Area
Narcotic Antagonists
Dopaminergic Neurons
Drug-Seeking Behavior
Cocaine-Related Disorders
Inhibitory Postsynaptic Potentials
Neuronal Plasticity
Aptitude
Mesencephalon
Reward
Dehydration
gamma-Aminobutyric Acid
Sprague Dawley Rats
Pharmacology

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Polter, Abigail M. ; Bishop, Rachel A. ; Briand, Lisa A. ; Graziane, Nicholas ; Pierce, R. Christopher ; Kauer, Julie A. / Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. In: Biological Psychiatry. 2014 ; Vol. 76, No. 10. pp. 785-793.
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Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. / Polter, Abigail M.; Bishop, Rachel A.; Briand, Lisa A.; Graziane, Nicholas; Pierce, R. Christopher; Kauer, Julie A.

In: Biological Psychiatry, Vol. 76, No. 10, 01.01.2014, p. 785-793.

Research output: Contribution to journalArticle

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T1 - Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking

AU - Polter, Abigail M.

AU - Bishop, Rachel A.

AU - Briand, Lisa A.

AU - Graziane, Nicholas

AU - Pierce, R. Christopher

AU - Kauer, Julie A.

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N2 - 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 selfadministration 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.

AB - 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 selfadministration 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.

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