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

ABSTRACT: 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.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 (?ORs) 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.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 ?ORs. Even pharmacological block of ?ORs beginning 4 days after stress has occurred reversed the block of LTPGABA. Administration of a ?ORs antagonist following stress prevents reinstatement of cocaine-seeking behavior.A brief stressor produces changes in the reward circuitry lasting several days. Our findings reveal roles for glucocorticoid receptors and ?ORs as mediators of the lasting effects of stress on synaptic plasticity. ?ORs antagonists reverse the neuroadaptations underlying stress-induced drug-seeking behavior and may be useful in the treatment of cocaine addiction.

SUBMITTER: Polter AM

PROVIDER: S-EPMC4240751 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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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 AM Bishop Rachel A RA Briand Lisa A LA Graziane Nicholas M NM Pierce R Christopher RC Kauer Julie A JA

Biological psychiatry 20140521 10

<h4>Background</h4>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.<h4>Methods</h4>Sprague- ...[more]

PMID: 24957331

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Project description:Background and purposeThe macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) is a multifunctional μ-opioid receptor and κ-opioid receptor agonist and κ-opioid receptor antagonist that produces antinociception and prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference (CPP). We hypothesized that an analogue of CJ-15,208, cyclo[Pro-Sar-Phe-d-Phe], would demonstrate multifunctional μ-opioid receptor and κ-opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective μ-opioid receptor agonists, while preventing both drug- and stress-induced reinstatement of morphine-induced CPP.Experimental approachThe opioid receptor agonist and antagonist activity of cyclo[Pro-Sar-Phe-d-Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor "knockout" mice using the 55°C warm-water tail-withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo[Pro-Sar-Phe-d-Phe] to block morphine- and stress-induced reinstatement of extinguished CPP was determined.Key resultscyclo[Pro-Sar-Phe-d-Phe] demonstrated dose-dependent, short-lasting antinociception, with an ED50 (and 95% confidence interval) of 0.15 (0.05-0.21) nmol i.c.v. and 1.91 (0.40-3.54) mg·kg-1 i.p., mediated by μ- and κ-opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose-dependent κ-opioid receptor antagonist-like activity at 2.5, but not at 4.5, h after administration. cyclo[Pro-Sar-Phe-d-Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ-receptors. Pretreatment with cyclo[Pro-Sar-Phe-d-Phe] prevented stress- and drug-induced reinstatement of extinguished morphine-place preference responses in a time-dependent manner.Conclusions and implicationsThese data suggest that cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug- and stress-induced relapse in morphine-abstinent subjects.

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

Publications

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

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