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Kappa opioid receptor and dynorphin signaling in the central amygdala regulates alcohol intake

Molecular Psychiatry volume 26, pages 2187–2199 (2021)Cite this article

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Abstract

Excessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

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Fig. 1: PDYN and KOR expression in CeA neurons is unaltered by a history of ethanol drinking.
Fig. 2: Knockout of KOR in CeA decreases ethanol consumption in male, but not female mice.
Fig. 3: PDYN knockout in CeA decreases ethanol consumption in male and female mice.
Fig. 4: Ethanol drinking does not alter synaptic transmission onto CeA PDYN neurons.
Fig. 5: Ethanol drinking alters the excitability of PDYN neurons in a sex-specific manner.

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References

  1. Sacks JJ, Gonzales KR, Bouchery EE, Tomedi LE, Brewer RD. 2010 national and state costs of excessive alcohol consumption. Am J Prev Med. 2015;49:e73–9.

    Article  PubMed  Google Scholar 

  2. Jennison KM. The short‐term effects and unintended long‐term consequences of binge drinking in college: a 10‐year follow‐up study. Am J Drug Alcohol Abuse. 2004;30:659–84.

    Article  PubMed  Google Scholar 

  3. McCarty CA, Ebel BE, Garrison MM, DiGiuseppe DL, Christakis DA, Rivara FP. Continuity of binge and harmful drinking from late adolescence to early adulthood. Pediatrics. 2004;114:714–9.

    Article  PubMed  Google Scholar 

  4. Lowery-Gionta EG, Navarro M, Li C, Pleil KE, Rinker JA, Cox BR, et al. Corticotropin releasing factor signaling in the central amygdala is recruited during binge-like ethanol consumption in C57BL/6J mice. J Neurosci. 2012;32:3405–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alheid GF, Heimer L. New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience. 1988;27:1–39.

    Article  CAS  PubMed  Google Scholar 

  6. Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, et al. NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci. 2015;18:545–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rinker JA, Marshall SA, Mazzone CM, Lowery-Gionta EG, Gulati V, Pleil KE, et al. Extended amygdala to ventral tegmental area corticotropin-releasing factor circuit controls binge ethanol intake. Biol Psychiatry. 2017;81:930–40.

    Article  CAS  PubMed  Google Scholar 

  8. Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the “dark side” of drug addiction. Nat Neurosci. 2005;8:1442–4.

    Article  CAS  PubMed  Google Scholar 

  9. Lin S, Boey D, Lee N, Schwarzer C, Sainsbury A, Herzog H. Distribution of prodynorphin mRNA and its interaction with the NPY system in the mouse brain. Neuropeptides. 2006;40:115–23.

    Article  CAS  PubMed  Google Scholar 

  10. Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 1995;18:22–9.

    Article  CAS  PubMed  Google Scholar 

  11. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa opiate receptors. Science. 1986;233:774–6.

    Article  CAS  PubMed  Google Scholar 

  12. Vijay A, Cavallo D, Goldberg A, Laat B, de, Nabulsi N, Huang Y, et al. PET imaging reveals lower kappa opioid receptor availability in alcoholics but no effect of age. Neuropsychopharmacology. 2018;43:2539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Walker BM, Koob GF. Pharmacological evidence for a motivational role of κ-opioid systems in ethanol dependence. Neuropsychopharmacology. 2007;33:643–52.

    Article  PubMed  CAS  Google Scholar 

  14. Anderson RI, Lopez MF, Becker HC. Stress-induced enhancement of ethanol intake in C57BL/6J mice with a history of chronic ethanol exposure: involvement of kappa opioid receptors. Front Cell Neurosci. 2016;45:1–10.

  15. Valdez GR, Harshberger E. Kappa opioid regulation of anxiety-like behavior during acute ethanol withdrawal. Pharmacol Biochem Behav. 2012;102:44–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, et al. The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry. 2014;75:774–82.

    Article  CAS  PubMed  Google Scholar 

  17. Anderson RI, Lopez MF, Griffin WC, Haun HL, Bloodgood DW, Pati D, et al. Dynorphin-kappa opioid receptor activity in the central amygdala modulates binge-like alcohol drinking in mice. Neuropsychopharmacology. 2018;44:1084-92.

  18. Kim J, Zhang X, Muralidhar S, LeBlanc SA, Tonegawa S. Basolateral to central amygdala neural circuits for appetitive behaviors. Neuron. 2017;93:1464–.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pomrenze MB, Millan EZ, Hopf FW, Keiflin R, Maiya R, Blasio A, et al. A transgenic rat for investigating the anatomy and function of corticotrophin releasing factor circuits. Neuroendocr Sci. 2015;9:487.

    Google Scholar 

  20. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. 2014;507:238–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chefer VI, Bäckman CM, Gigante ED, Shippenberg TS. Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion. Neuropsychopharmacology. 2013;38:2623–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC. Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice. Physiol Behav. 2005;84:53–63.

    Article  CAS  PubMed  Google Scholar 

  23. Hwa LS, Chu A, Levinson SA, Kayyali TM, DeBold JF, Miczek KA. Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol. Alcohol Clin Exp Res. 2011;35:1938–47.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Blednov YA, Walker D, Martinez M, Harris RA. Reduced alcohol consumption in mice lacking preprodynorphin. Alcohol. 2006;40:73–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kovacs KM, Szakall I, O’Brien D, Wang R, Vinod KY, Saito M, et al. Decreased oral self-administration of alcohol in κ-opioid receptor knock-out mice. Alcohol Clin Exp Res. 2005;29:730–8.

    Article  CAS  PubMed  Google Scholar 

  26. Crowley NA, Bloodgood DW, Hardaway JA, Kendra AM, McCall JG, Al-Hasani R, et al. Dynorphin controls the gain of an amygdalar anxiety circuit. Cell Rep. 2016. http://www.cell.com/article/S2211124716302042/abstract.

  27. Funk CK, O’Dell LE, Crawford EF, Koob GF. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci. 2006;26:11324–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sparrow AM, Lowery-Gionta EG, Pleil KE, Li C, Sprow GM, Cox BR, et al. Central neuropeptide Y modulates binge-like ethanol drinking in C57BL/6J mice via Y1 and Y2 receptors. Neuropsychopharmacology. 2012;37:1409–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Anderson RI, Becker HC. Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol. Alcohol Clin Exp Res. 2017;41:1402–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou Y, Crowley RS, Ben K, Prisinzano TE, Kreek MJ. Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone. Brain Res. 2017;1662:75–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Russell SE, Rachlin AB, Smith KL, Muschamp J, Berry L, Zhao Z, et al. Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats. Biol Psychiatry. 2014;76:213–22.

    Article  CAS  PubMed  Google Scholar 

  32. Van’t Veer A, Smith KL, Cohen BM, Carlezon WA, Bechtholt AJ. Kappa-opioid receptors differentially regulate low and high levels of ethanol intake in female mice. Brain Behav. 2016;6:e00523.

  33. Gilpin NW, Roberto M, Koob GF, Schweitzer P. Kappa opioid receptor activation decreases inhibitory transmission and antagonizes alcohol effects in rat central amygdala. Neuropharmacology. 2014;77:294–302.

    Article  CAS  PubMed  Google Scholar 

  34. Kang-Park M, Kieffer BL, Roberts AJ, Siggins GR, Moore SD. κ-opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. J Pharmacol Exp Ther. 2013;346:130–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pleil KE, Lowery-Gionta EG, Crowley NA, Li C, Marcinkiewcz CA, Rose JH, et al. Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala. Neuropharmacology. 2015;99:735–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Roberto M, Madamba SG, Stouffer DG, Parsons LH, Siggins GR. Increased GABA release in the central amygdala of ethanol-dependent rats. J Neurosci. 2004;24:10159–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Roberto M, Schweitzer P, Madamba SG, Stouffer DG, Parsons LH, Siggins GR. Acute and chronic ethanol alter glutamatergic transmission in rat central amygdala: an in vitro and in vivo analysis. J Neurosci. 2004;24:1594–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Herman MA, Contet C, Roberto M. A functional switch in tonic GABA currents alters the output of central amygdala corticotropin releasing factor receptor-1 neurons following chronic ethanol exposure. J Neurosci. 2016;36:10729–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Heilig M, Egli M. Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006;111:855–76.

    Article  CAS  PubMed  Google Scholar 

  40. Carroll FI, Carlezon WA. Development of κ opioid receptor antagonists. J Med Chem. 2013;56:2178–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chavkin C, Koob GF. Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacol N Y. 2016;41:373–4.

    Article  CAS  Google Scholar 

  42. Crowley NA, Kash TL. Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2015;62:51–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Abraham AD, Schattauer SS, Reichard KL, Cohen JH, Fontaine HM, Song AJ, et al. Estrogen regulation of GRK2 inactivates kappa opioid receptor signaling mediating analgesia, but not aversion. J Neurosci. 2018;38:8031–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Overstreet DH, Knapp DJ, Breese GR. Similar anxiety-like responses in male and female rats exposed to repeated withdrawals from ethanol. Pharmacol Biochem Behav. 2004;78:459–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rose JH, Karkhanis AN, Chen R, Gioia D, Lopez MF, Becker HC, et al. Supersensitive kappa opioid receptors promotes ethanol withdrawal-related behaviors and reduce dopamine signaling in the nucleus accumbens. Int J Neuropsychopharmacol. 2016;19:1–10.

  46. Cox BR, Olney JJ, Lowery-Gionta EG, Sprow GM, Rinker JA, Navarro M, et al. Repeated cycles of binge-like ethanol drinking in male C57BL/6J mice augments subsequent voluntary ethanol intake but not other dependence-like phenotypes. Alcohol Clin Exp Res. 2013;37:1688–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee KM, Coelho MA, Class MA, Szumlinski KK. mGlu5-dependent modulation of anxiety during early withdrawal from binge-drinking in adult and adolescent male mice. Drug Alcohol Depend. 2018;184:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Becker HC, Hale RL. Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: an animal model of alcohol withdrawal “Kindling”. Alcohol Clin Exp Res. 1993;17:94–8.

    Article  CAS  PubMed  Google Scholar 

  49. Erikson CM, Wei G, Walker BM. Maladaptive behavioral regulation in alcohol dependence: role of kappa-opioid receptors in the bed nucleus of the stria terminalis. Neuropharmacology. 2018;140:162–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Guglielmo G, de, Kallupi M, Pomrenze MB, Crawford E, Simpson S, Schweitzer P, et al. Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats. Nat Commun. 2019;10:1238.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Al-Hasani R, McCall JG, Shin G, Gomez AM, Schmitz GP, Bernardi JM, et al. Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron. 2015;87:1063–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Castro DC, Berridge KC. Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness “liking” and “wanting”. J Neurosci. 2014;34:4239–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tejeda HA, Wu J, Kornspun AR, Pignatelli M, Kashtelyan V, Krashes MJ, et al. Pathway- and cell-specific kappa-opioid receptor modulation of excitation-inhibition balance differentially gates D1 and D2 accumbens neuron activity. Neuron. 2017;93:147–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li C, Pleil KE, Stamatakis AM, Busan S, Vong L, Lowell BB, et al. Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling. Biol Psychiatry. 2012;71:725–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bohn LM, Aubé J. Seeking (and Finding) biased ligands of the kappa opioid receptor. ACS Med Chem Lett. 2017;8:694–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brust TF, Morgenweck J, Kim SA, Rose JH, Locke JL, Schmid CL, et al. Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Sci Signal. 2016;9:ra117–ra117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Ho J-H, Stahl EL, Schmid CL, Scarry SM, Aubé J, Bohn LM. G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons. Sci Signal. 2018;11:eaar4309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We would like to thank Christina Catavero for assistance with histology. We would also like to thank Maria Luisa Torruella-Suarez and Zoe McElligott for thoughtful discussion.

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, Curriculum in Neuroscience, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Daniel W. Bloodgood, Sofia Neira & Thomas L. Kash

  2. Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Daniel W. Bloodgood, J. Andrew Hardaway, Christina M. Stanhope, Dipanwita Pati, Melanie M. Pina, Sofia Neira, Kristen M. Boyt & Thomas L. Kash

  3. Department of Biology, University of North Carolina College of Arts and Sciences, Chapel Hill, NC, USA

    Shivani Desai

  4. Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA, USA

    Richard D. Palmiter

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Bloodgood, D.W., Hardaway, J.A., Stanhope, C.M. et al. Kappa opioid receptor and dynorphin signaling in the central amygdala regulates alcohol intake. Mol Psychiatry 26, 2187–2199 (2021). https://doi.org/10.1038/s41380-020-0690-z

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