Advertisement

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 (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.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Piazza P.V.
        • Deminiere J.M.
        • le Moal M.
        • Simon H.
        Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration.
        Brain Res. 1990; 514: 22-26
        • Ramsey N.F.
        • Van Ree J.M.
        Emotional but not physical stress enhances intravenous cocaine self-administration in drug-naive rats.
        Brain Res. 1993; 608: 216-222
        • Goeders N.E.
        • Guerin G.F.
        Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats.
        Psychopharmacology. 1994; 114: 63-70
        • Shaham Y.
        • Stewart J.
        Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats.
        Psychopharmacology. 1994; 114: 523-527
        • Haney M.
        • Maccari S.
        • Le Moal M.
        • Simon H.
        • Piazza P.V.
        Social stress increases the acquisition of cocaine self-administration in male and female rats.
        Brain Res. 1995; 698: 46-52
        • Shaham Y.
        • Shalev U.
        • Lu L.
        • De Wit H.
        • Stewart J.
        The reinstatement model of drug relapse: History, methodology and major findings.
        Psychopharmacology. 2003; 168: 3-20
        • Le A.D.
        • Quan B.
        • Juzytch W.
        • Fletcher P.J.
        • Joharchi N.
        • Shaham Y.
        Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats.
        Psychopharmacology. 1998; 135: 169-174
        • Shaham Y.
        • Rodaros D.
        • Stewart J.
        Reinstatement of heroin-reinforced behavior following long-term extinction: Implications for the treatment of relapse to drug taking.
        Behav Pharmacol. 1994; 5: 360-364
        • Erb S.
        • Shaham Y.
        • Stewart J.
        Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period.
        Psychopharmacology. 1996; 128: 408-412
        • Shaham Y.
        • Stewart J.
        Stress reinstates heroin-seeking in drug-free animals: An effect mimicking heroin, not withdrawal.
        Psychopharmacology. 1995; 119: 334-341
        • Conrad K.
        • James E.M.
        • Lindsay M.C.
        • Kerstin A.F.
        • Mitch B.
        • Michela M.
        Persistent increases in cocaine-seeking behavior after acute exposure to cold swim stress.
        Biol Psychiatry. 2010; 68: 303-305
        • Fields H.L.
        • Hjelmstad G.O.
        • Margolis E.B.
        • Nicola S.M.
        Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement.
        Annu Rev Neurosci. 2007; 30: 289-316
        • Kauer J.A.
        • Malenka R.C.
        Synaptic plasticity and addiction.
        Nat Rev Neurosci. 2007; 8: 844-858
        • Koob G.F.
        • Volkow N.D.
        Neurocircuitry of addiction.
        Neuropsychopharmacology. 2010; 35: 217-238
        • Wise R.A.
        • Morales M.
        A ventral tegmental CRF-glutamate-dopamine interaction in addiction.
        Brain Res. 2010; 1314: 38-43
        • Luscher C.
        • Malenka R.C.
        Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling.
        Neuron. 2011; 69: 650-663
        • Polter A.M.
        • Kauer J.A.
        Stress and VTA synapses: Implications for addiction and depression.
        Eur J Neurosci. 2014; 39: 1179-1188
        • Tidey J.W.
        • Miczek K.A.
        Social defeat stress selectively alters mesocorticolimbic dopamine release: An in vivo microdialysis study.
        Brain Res. 1996; 721: 140-149
        • Anstrom K.K.
        • Woodward D.J.
        Restraint increases dopaminergic burst firing in awake rats.
        Neuropsychopharmacology. 2005; 30: 1832-1840
        • Ungless M.A.
        • Argilli E.
        • Bonci A.
        Effects of stress and aversion on dopamine neurons: implications for addiction.
        Neurosci Biobehav Rev. 2010; 35: 151-156
        • Brischoux F.
        • Chakraborty S.
        • Brierley D.I.
        • Ungless M.A.
        Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli.
        Proc Natl Acad Sci U S A. 2009; 106: 4894-4899
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Saal D.
        • Dong Y.
        • Bonci A.
        • Malenka R.C.
        Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.
        Neuron. 2003; 37: 577-582
        • Dong Y.
        • Saal D.
        • Thomas M.
        • Faust R.
        • Bonci A.
        • Robinson T.
        • et al.
        Cocaine-induced potentiation of synaptic strength in dopamine neurons: Behavioral correlates in GluRA(-/-) mice.
        Proc Natl Acad Sci U S A. 2004; 101: 14282-14287
        • Graziane N.M.
        • Polter A.M.
        • Briand L.A.
        • Pierce R.C.
        • Kauer J.A.
        Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity.
        Neuron. 2013; 77: 942-954
        • Daftary S.S.
        • Panksepp J.
        • Dong Y.
        • Saal D.B.
        Stress-induced, glucocorticoid-dependent strengthening of glutamatergic synaptic transmission in midbrain dopamine neurons.
        Neurosci Lett. 2009; 452: 273-276
        • Ungless M.A.
        • Whistler J.L.
        • Malenka R.C.
        • Bonci A.
        Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.
        Nature. 2001; 411: 583-587
        • Bellone C.
        • Luscher C.
        Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression.
        Nat Neurosci. 2006; 9: 636-641
        • Chen B.T.
        • Bowers M.S.
        • Martin M.
        • Hopf F.W.
        • Guillory A.M.
        • Carelli R.M.
        • et al.
        Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA.
        Neuron. 2008; 59: 288-297
        • Niehaus J.
        • Murali M.
        • Kauer J.
        Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area.
        Eur J Neurosci. 2010; 32: 108-117
        • Nugent F.
        • Penick E.
        • Kauer J.
        Opioids block long-term potentiation of inhibitory synapses.
        Nature. 2007; 446: 1086-1090
        • Nugent F.S.
        • Niehaus J.L.
        • Kauer J.A.
        PKG and PKA signaling in LTP at GABAergic synapses.
        Neuropsychopharmacology. 2009; 34: 1829-1842
        • Lammel S.
        • Hetzel A.
        • Hackel O.
        • Jones I.
        • Liss B.
        • Roeper J.
        Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system.
        Neuron. 2008; 57: 760-773
        • Margolis E.B.
        • Lock H.
        • Hjelmstad G.O.
        • Fields H.L.
        The ventral tegmental area revisited: Is there an electrophysiological marker for dopaminergic neurons?.
        J Physiol. 2006; 577: 907-924
        • Jain S.
        • Bruot B.C.
        • Stevenson J.R.
        Cold swim stress leads to enhanced splenocyte responsiveness to concanavalin A, decreased serum testosterone, and increased serum corticosterone, glucose, and protein.
        Life Sci. 1996; 59: 209-218
        • Wittmann W.
        • Schunk E.
        • Rosskothen I.
        • Gaburro S.
        • Singewald N.
        • Herzog H.
        • et al.
        Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone.
        Neuropsychopharmacology. 2009; 34: 775-785
        • Bilkei-Gorzo A.
        • Racz I.
        • Michel K.
        • Mauer D.
        • Zimmer A.
        • Klingmuller D.
        • et al.
        Control of hormonal stress reactivity by the endogenous opioid system.
        Psychoneuroendocrinology. 2008; 33: 425-436
        • McLaughlin J.P.
        • Land B.B.
        • Li S.
        • Pintar J.E.
        • Chavkin C.
        Prior activation of kappa opioid receptors by U50,488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning.
        Neuropsychopharmacology. 2006; 31: 787-794
        • Borgland S.L.
        • Malenka R.C.
        • Bonci A.
        Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: Electrophysiological and behavioral correlates in individual rats.
        J Neurosci. 2004; 24: 7482-7490
        • Harfstrand A.
        • Fuxe K.
        • Cintra A.
        • Agnati L.F.
        • Zini I.
        • Wikstrom A.C.
        • et al.
        Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain.
        Proc Natl Acad Sci U S A. 1986; 83: 9779-9783
        • Hensleigh E.
        • Pritchard L.M.
        Glucocorticoid receptor expression and sub-cellular localization in dopamine neurons of the rat midbrain.
        Neurosci Lett. 2013; 556: 191-195
        • Deroche V.
        • Marinelli M.
        • Le Moal M.
        • Piazza P.V.
        Glucocorticoids and behavioral effects of psychostimulants. II: Cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels.
        J Pharmacol Exp Therap. 1997; 281: 1401-1407
        • Shaham Y.
        • Funk D.
        • Erb S.
        • Brown T.J.
        • Walker C.D.
        • Stewart J.
        Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats.
        J Neurosci. 1997; 17: 2605-2614
        • Ambroggi F.
        • Turiault M.
        • Milet A.
        • Deroche-Gamonet V.
        • Parnaudeau S.
        • Balado E.
        • et al.
        Stress and addiction: Glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking.
        Nat Neurosci. 2009; 12: 247-249
        • Van’t Veer A.
        • Carlezon Jr, W.A.
        Role of kappa-opioid receptors in stress and anxiety-related behavior.
        Psychopharmacology. 2013; 229: 435-452
        • Bruchas M.R.
        • Land B.B.
        • Chavkin C.
        The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors.
        Brain Res. 2010; 1314: 44-55
        • Margolis E.B.
        • Hjelmstad G.O.
        • Bonci A.
        • Fields H.L.
        Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons.
        J Neurophysiol. 2005; 93: 3086-3093
        • Ford C.P.
        • Mark G.P.
        • Williams J.T.
        Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location.
        J Neurosci. 2006; 26: 2788-2797
        • Ford C.P.
        • Beckstead M.J.
        • Williams J.T.
        Kappa opioid inhibition of somatodendritic dopamine inhibitory postsynaptic currents.
        J Neurophysiol. 2007; 97: 883-891
        • Beardsley P.
        • Howard J.
        • Shelton K.
        • Carroll F.
        Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats.
        Psychopharmacology. 2005; 183: 118-126
        • Carey A.
        • Borozny K.
        • Aldrich J.
        • McLaughlin J.
        Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn.
        Eur J Pharmacol. 2007; 569: 84-89
        • Redila V.
        • Chavkin C.
        Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system.
        Psychopharmacology. 2008; 200: 59-70
        • Sperling R.E.
        • Gomes S.M.
        • Sypek E.I.
        • Carey A.N.
        • McLaughlin J.P.
        Endogenous kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place preference and self-administration.
        Psychopharmacology. 2010; 210: 199-209
        • Al-Hasani R.
        • McCall J.G.
        • Foshage A.M.
        • Bruchas M.R.
        Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism.
        Neuropsychopharmacology. 2013; 38: 2484-2497
        • Land B.B.
        • Bruchas M.R.
        • Schattauer S.
        • Giardino W.J.
        • Aita M.
        • Messinger D.
        • et al.
        Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking.
        Proc Natl Acad Sci U S A. 2009; 106: 19168-19173
        • Margolis E.B.
        • Lock H.
        • Chefer V.I.
        • Shippenberg T.S.
        • Hjelmstad G.O.
        • Fields H.L.
        Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex.
        Proc Natl Acad Sci U S A. 2006; 103: 2938-2942
        • Land B.B.
        • Bruchas M.R.
        • Lemos J.C.
        • Xu M.
        • Melief E.J.
        • Chavkin C.
        The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system.
        J Neurosci. 2008; 28: 407-414
        • Watanabe Y.
        • Weiland N.G.
        • McEwen B.S.
        Effects of adrenal steroid manipulations and repeated restraint stress on dynorphin mRNA levels and excitatory amino acid receptor binding in hippocampus.
        Brain Research. 1995; 680: 217-225
        • Paladini C.A.
        • Tepper J.M.
        GABA(A) and GABA(B) antagonists differentially affect the firing pattern of substantia nigra dopaminergic neurons in vivo.
        Synapse. 1999; 32: 165-176
        • Johnson S.W.
        • North R.A.
        Two types of neurone in the rat ventral tegmental area and their synaptic inputs.
        J Physiol. 1992; 450: 455-468
        • Tan K.R.
        • Yvon C.
        • Turiault M.
        • Mirzabekov J.J.
        • Doehner J.
        • Labouebe G.
        • et al.
        GABA neurons of the VTA drive conditioned place aversion.
        Neuron. 2012; 73: 1173-1183
        • van Zessen R.
        • Phillips J.L.
        • Budygin E.A.
        • Stuber G.D.
        Activation of VTA GABA neurons disrupts reward consumption.
        Neuron. 2012; 73: 1184-1194
        • Grace A.A.
        • Onn S.P.
        Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro.
        J Neurosci. 1989; 9: 3463-3481
        • Lecca S.
        • Melis M.
        • Luchicchi A.
        • Muntoni A.L.
        • Pistis M.
        Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse.
        Neuropsychopharmacology. 2012; 37: 1164-1176
        • Matsui A.
        • Williams J.T.
        Opioid-sensitive GABA inputs from rostromedial tegmental nucleus synapse onto midbrain dopamine neurons.
        J Neurosci. 2011; 31: 17729-17735
        • Jennings J.H.
        • Sparta D.R.
        • Stamatakis A.M.
        • Ung R.L.
        • Pleil K.E.
        • Kash T.L.
        • et al.
        Distinct extended amygdala circuits for divergent motivational states.
        Nature. 2013; 496: 224-228
        • Lammel S.
        • Lim B.K.
        • Malenka R.C.
        Reward and aversion in a heterogeneous midbrain dopamine system.
        Neuropharmacology. 2014; 76: 351-359
        • McFarland K.
        • Davidge S.B.
        • Lapish C.C.
        • Kalivas P.W.
        Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior.
        J Neurosci. 2004; 24: 1551-1560
        • Nestler E.J.
        • Carlezon Jr., W.A.
        The mesolimbic dopamine reward circuit in depression.
        Biol Psychiatry. 2006; 59: 1151-1159
        • Briand L.A.
        • Vassoler F.M.
        • Pierce R.C.
        • Valentino R.J.
        • Blendy J.A.
        Ventral tegmental afferents in stress-induced reinstatement: The role of cAMP response element-binding protein.
        J Neurosci. 2010; 30: 16149-16159
        • Lammel S.
        • Ion D.I.
        • Roeper J.
        • Malenka R.C.
        Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli.
        Neuron. 2011; 70: 855-862
        • Lammel S.
        • Lim B.K.
        • Ran C.
        • Huang K.W.
        • Betley M.J.
        • Tye K.M.
        • et al.
        Input-specific control of reward and aversion in the ventral tegmental area.
        Nature. 2012; 491: 212-217
        • Kreek M.J.
        • Zhou Y.
        • Butelman E.R.
        • Levran O.
        Opiate and cocaine addiction: From bench to clinic and back to the bench.
        Curr Opin Pharmacol. 2009; 9: 74-80
        • Shippenberg T.S.
        The dynorphin/kappa opioid receptor system: A new target for the treatment of addiction and affective disorders?.
        Neuropsychopharmacology. 2009; 34: 247
        • Wee S.
        • Koob G.F.
        The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse.
        Psychopharmacology (Berl). 2010; 210: 121-135
        • Smith J.S.
        • Schindler A.G.
        • Martinelli E.
        • Gustin R.M.
        • Bruchas M.R.
        • Chavkin C.
        Stress-induced activation of the dynorphin/kappa-opioid receptor system in the amygdala potentiates nicotine conditioned place preference.
        J Neurosci. 2012; 32: 1488-1495
        • Chen A.C.
        • LaForge K.S.
        • Ho A.
        • McHugh P.F.
        • Kellogg S.
        • Bell K.
        • et al.
        Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse.
        Am J Med Genet. 2002; 114: 429-435
        • Dahl J.P.
        • Weller A.E.
        • Kampman K.M.
        • Oslin D.W.
        • Lohoff F.W.
        • Ferraro T.N.
        • et al.
        Confirmation of the association between a polymorphism in the promoter region of the prodynorphin gene and cocaine dependence.
        Am J Med Genet B Neuropsychiatr Genet. 2005; 139B: 106-108
        • Williams T.J.
        • LaForge K.S.
        • Gordon D.
        • Bart G.
        • Kellogg S.
        • Ott J.
        • et al.
        Prodynorphin gene promoter repeat associated with cocaine/alcohol codependence.
        Addict Biol. 2007; 12: 496-502
        • Hurd Y.L.
        • Herkenham M.
        Molecular alterations in the neostriatum of human cocaine addicts.
        Synapse. 1993; 13: 357-369

      Linked Article

      • How Does Stress-Induced Activation of the Kappa Opioid System Increase Addiction Risk?
        Biological PsychiatryVol. 76Issue 10
        • Preview
          In their article in this issue of Biological Psychiatry, Polter et al. (1) show that cold-water swim stress exposure blocks long-term potentiation of GABAergic synaptic input (LTPGABA) recorded in ventral tegmental area (VTA) dopamine neurons of male Sprague-Dawley rats. The effects of stress exposure on LTPGABA were blocked by pretreatment with the glucocorticoid antagonist RU-486 or the kappa opioid receptor (KOR) antagonist norbinaltorphimine (norBNI). When norBNI was given 4 days after stress exposure, it reversed the effects of swim stress on LTPGABA and blocked stress-induced reinstatement of cocaine self-administration.
        • Full-Text
        • PDF