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Interneuronal δ-GABAA receptors regulate binge drinking and are necessary for the behavioral effects of early withdrawal

Abstract

Extensive evidence points to a role for GABAergic signaling in the amygdala in mediating the effects of alcohol, including presynaptic changes in GABA release, suggesting effects on GABAergic neurons. However, the majority of studies focus solely on the effects of alcohol on principal neurons. Here we demonstrate that δ-GABAARs, which have been suggested to confer ethanol sensitivity, are expressed at a high density on parvalbumin (PV) interneurons in the basolateral amygdala (BLA). Thus, we hypothesized that δ-GABAARs on PV interneurons may represent both an initial pharmacological target for alcohol and a site for plasticity associated with the expression of various behavioral maladaptations during withdrawal from binge drinking. To investigate this, we used a mouse model of voluntary alcohol intake (Drinking-in-the-Dark-Multiple Scheduled Access) to induce escalating heavy binge drinking and anxiety-like behavior in mice. This pattern of intake was associated with increased δ protein expression on parvalbumin positive interneurons in both the BLA and hippocampus. Loss of δ-GABAARs specifically in PV interneurons (PV:δ−/−) increased binge drinking behavior, reduced sensitivity to alcohol-induced motor incoordination, enhanced sensitivity to alcohol-induced hyperlocomotion and blocked the expression of withdrawal from binge drinking. This study is the first to demonstrate a role for δGABAARs specifically in PV-expressing interneurons in modulating binge alcohol intake and withdrawal-induced anxiety.

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References

  1. 1.

    Organization WH (2014). Global status report on alcohol and health, 2014 World Health Organization.

  2. 2.

    Esser MB, Hedden SL, Kanny D, Brewer RD, Gfroerer JC, Naimi TS. Prevalence of alcohol dependence among US adult drinkers, 2009-2011. Prev Chronic Dis. 2014;11:1–11.

  3. 3.

    Paljärvi T, Koskenvuo M, Poikolainen K, Kauhanen J, Sillanmäki L, Mäkelä P. Binge drinking and depressive symptoms: a 5‐year population‐based cohort study. Addiction. 2009;104:1168–78.

  4. 4.

    Townshend JM, Duka T. Binge drinking, cognitive performance and mood in a population of young social drinkers. Alcohol: Clin Exp Res. 2005;29:317–25.

  5. 5.

    Lee K, Coelho M, Sern K, Szumlinski K. Homer2 within the central nucleus of the amygdala modulates withdrawal-induced anxiety in a mouse model of binge-drinking. Neuropharmacology. 2018;128:448–59.

  6. 6.

    Lee KM, Coehlo M, McGregor HA, Waltermire RS, Szumlinski KK. Binge alcohol drinking elicits persistent negative affect in mice. Behav Brain Res. 2015;291:385–98.

  7. 7.

    Stevenson JR, Schroeder JP, Nixon K, Besheer J, Crews FT, Hodge CW. Abstinence following alcohol drinking produces depression-like behavior and reduced hippocampal neurogenesis in mice. Neuropsychopharmacology. 2009;34:1209–22.

  8. 8.

    Fleming RL, Acheson SK, Moore SD, Wilson WA, Swartzwelder HS. GABA transport modulates the ethanol sensitivity of tonic inhibition in the rat dentate gyrus. Alcohol. 2011;45:577–83.

  9. 9.

    Fleming RL, Wilson WA, Swartzwelder HS. Magnitude and ethanol sensitivity of tonic GABAA receptor-mediated inhibition in dentate gyrus changes from adolescence to adulthood. J Neurophysiol. 2007;97:3806–11.

  10. 10.

    Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I. A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci. 2007;10:40–8.

  11. 11.

    Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M. Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity. Nat Neurosci. 2005;8:339–45.

  12. 12.

    Liang J, Zhang N, Cagetti E, Houser CR, Olsen RW, Spigelman I. Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J Neurosci. 2006;26:1749–58.

  13. 13.

    Lindemeyer AK, Liang J, Marty VN, Meyer EM, Suryanarayanan A, Olsen RW, et al. Ethanol-induced plasticity of GABAA receptors in the basolateral amygdala. Neurochem Res. 2014;39:1162–70.

  14. 14.

    Centanni SW, Burnett EJ, Trantham-Davidson H, Chandler LJ. Loss of delta-GABAA receptor-mediated tonic currents in the adult prelimbic cortex following adolescent alcohol exposure. Addict Biol. 2017;22:616–28.

  15. 15.

    Wallner M, Hanchar HJ, Olsen RW. Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci USA. 2003;100:15218–23.

  16. 16.

    Wei W, Faria LC, Mody I. Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci. 2004;24:8379–82.

  17. 17.

    Nie H, Rewal M, Gill TM, Ron D, Janak PH. Extrasynaptic delta-containing GABAA receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake. Proc Natl Acad Sci USA. 2011;108:4459–64.

  18. 18.

    Ramaker MJ, Ford MM, Fretwell AM, Finn DA. Alteration of ethanol drinking in mice via modulation of the GABA(A) receptor with ganaxolone, finasteride, and gaboxadol. Alcohol Clin Exp Res. 2011;35:1994–2007.

  19. 19.

    Fritz BM, Boehm SL 2nd. Site-specific microinjection of Gaboxadol into the infralimbic cortex modulates ethanol intake in male C57BL/6J mice. Behav Brain Res. 2014;273:8–15.

  20. 20.

    Melón LC, Nolan ZT, Colar D, Moore EM, Boehm SL 2nd. Activation of extrasynaptic delta-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion. Horm Behav. 2017;95:65–75.

  21. 21.

    Moore EM, Serio KM, Goldfarb KJ, Stepanovska S, Linsenbardt DN, Boehm SL 2nd. GABAergic modulation of binge-like ethanol intake in C57BL/6J mice. Pharmacol Biochem Behav. 2007;88:105–13.

  22. 22.

    Finn DA, Jimenez VA. Dynamic adaptation in neurosteroid networks in response to alcohol. Handb Exp Pharmacol. 2017.

  23. 23.

    Porcu P, Morrow AL. Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies. Psychopharmacology. 2014;231:3257–72.

  24. 24.

    Cook JB, Werner DF, Maldonado-Devincci AM, Leonard MN, Fisher KR, O’Buckley TK, et al. Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration. J Neurosci. 2014b;34:5824–34.

  25. 25.

    Fleming RL, Acheson SK, Moore SD, Wilson WA, Swartzwelder HS. In the rat, chronic intermittent ethanol exposure during adolescence alters the ethanol sensitivity of tonic inhibition in adulthood. Alcohol Clin Exp Res. 2012;36:279–85.

  26. 26.

    Fleming RL, Li Q, Risher ML, Sexton HG, Moore SD, Wilson WA, et al. Binge-pattern ethanol exposure during adolescence, but not adulthood, causes persistent changes in GABAA receptor-mediated tonic inhibition in dentate granule cells. Alcohol Clin Exp Res. 2013;37:1154–60.

  27. 27.

    Liang J, Shen Y, Shao XM, Scott MB, Ly E, Wong S, et al. Dihydromyricetin prevents fetal alcohol exposure-induced behavioral and physiological deficits: the roles of GABAA receptors in adolescence. Neurochem Res. 2014b;39:1147–61.

  28. 28.

    Liang J, Lindemeyer AK, Suryanarayanan A, Meyer EM, Marty VN, Ahmad SO, et al. Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats. J Neurophysiol. 2014a;112:39–50.

  29. 29.

    Gatta E, Auta J, Gavin DP, Bhaumik DK, Grayson DR, Pandey SC, et al. Emerging role of one-carbon metabolism and DNA methylation enrichment on delta-containing GABAA receptor expression in the cerebellum of subjects with alcohol use disorders (AUD). Int J Neuropsychopharmacol. 2017;20:1013–26.

  30. 30.

    Shen Y, Lindemeyer AK, Spigelman I, Sieghart W, Olsen RW, Liang J. Plasticity of GABAA receptors after ethanol pre-exposure in cultured hippocampal neurons. Mol Pharmacol. 2011;79:432–42.

  31. 31.

    McDonald AJ, Mascagni F. Parvalbumin-containing interneurons in the basolateral amygdala express high levels of the alpha1 subunit of the GABAA receptor. J Comp Neurol. 2004;473:137–46.

  32. 32.

    Hale MW, Johnson PL, Westerman AM, Abrams JK, Shekhar A, Lowry CA. Multiple anxiogenic drugs recruit a parvalbumin-containing subpopulation of GABAergic interneurons in the basolateral amygdala. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1285–93.

  33. 33.

    Herman MA, Contet C, Justice NJ, Vale W, Roberto M. Novel subunit-specific tonic GABA currents and differential effects of ethanol in the central amygdala of CRF receptor-1 reporter mice. J Neurosci. 2013;33:3284–98.

  34. 34.

    Herman MA, Roberto M. Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addict Biol. 2016;21:72–86.

  35. 35.

    Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, et al. Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala Crhr1 expression following a history of dependence. Biol Psychiatry. 2008;63:139–45.

  36. 36.

    Lee V, Sarkar J, Maguire J. Loss of Gabrd in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors. Psychoneuroendocrinology. 2014;41:75–88.

  37. 37.

    Ferando I, Mody I. Altered gamma oscillations during pregnancy through loss of delta subunit-containing GABA(A) receptors on parvalbumin interneurons. Front Neural Circuits. 2013;7:144.

  38. 38.

    Ferando I, Mody I. In vitro gamma oscillations following partial and complete ablation of delta subunit-containing GABAA receptors from parvalbumin interneurons. Neuropharmacology. 2015;88:91–8.

  39. 39.

    Bell RL, Rodd ZA, Smith RJ, Toalston JE, Franklin KM, McBride WJ. Modeling binge-like ethanol drinking by peri-adolescent and adult P rats. Pharmacol Biochem Behav. 2011;100:90–7.

  40. 40.

    Melon LC, Wray KN, Moore EM, Boehm SL 2nd. Sex and age differences in heavy binge drinking and its effects on alcohol responsivity following abstinence. Pharmacol Biochem Behav. 2013;104:177–87.

  41. 41.

    Sarkar J, Wakefield S, MacKenzie G, Moss SJ, Maguire J. Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors. J Neurosci. 2011;31:18198–210.

  42. 42.

    Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor plasticity during pregnancy. J Neurosci. 2009;29:9592–601.

  43. 43.

    Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.

  44. 44.

    Khisti RT, Kumar S, Morrow AL. Ethanol rapidly induces steroidogenic acute regulatory protein expression and translocation in rat adrenal gland. Eur J Pharmacol. 2003;473:225–7.

  45. 45.

    Kim HJ, Ha M, Park CH, Park SJ, Youn SM, Kang SS, et al. StAR and steroidogenic enzyme transcriptional regulation in the rat brain: effects of acute alcohol administration. Brain Res Mol Brain Res. 2003;115:39–49.

  46. 46.

    Serra M, Pisu MG, Floris I, Cara V, Purdy RH, Biggio G. Social isolation-induced increase in the sensitivity of rats to the steroidogenic effect of ethanol. J Neurochem. 2003;85:257–63.

  47. 47.

    Cook JB, Dumitru AM, O’Buckley TK, Morrow AL. Ethanol administration produces divergent changes in GABAergic neuroactive steroid immunohistochemistry in the rat brain. Alcohol Clin Exp Res. 2014a;38:90–9.

  48. 48.

    Morrow AL, Janis GC, VanDoren MJ, Matthews DB, Samson HH, Janak PH, et al. Neurosteroids mediate pharmacological effects of ethanol: a new mechanism of ethanol action? Alcohol Clin Exp Res. 1999;23:1933–40.

  49. 49.

    Porcu P, O’Buckley TK, Alward SE, Song SC, Grant KA, de Wit H, et al. Differential effects of ethanol on serum GABAergic 3alpha,5alpha/3alpha,5beta neuroactive steroids in mice, rats, cynomolgus monkeys, and humans. Alcohol Clin Exp Res. 2010;34:432–42.

  50. 50.

    Sanna E, Talani G, Busonero F, Pisu MG, Purdy RH, Serra M, et al. Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J Neurosci. 2004;24:6521–30.

  51. 51.

    Cagetti E, Liang J, Spigelman I, Olsen RW. Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol Pharmacol. 2003;63:53–64.

  52. 52.

    Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL, et al. GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res. 2001;25:1708–18.

  53. 53.

    Tonsfeldt KJ, Suchland KL, Beeson KA, Lowe JD, Li MH, Ingram SL. Sex differences in GABAA signaling in the periaqueductal gray induced by persistent inflammation. J Neurosci. 2016;36:1669–81.

  54. 54.

    Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci. 2005;8:797–804.

  55. 55.

    Lovick TA, Griffiths JL, Dunn SM, Martin IL. Changes in GABA(A) receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats. Neuroscience. 2005;131:397–405.

  56. 56.

    Wu X, Wu Z, Ning G, Guo Y, Ali R, Macdonald RL, et al. gamma-Aminobutyric acid type A (GABAA) receptor alpha subunits play a direct role in synaptic versus extrasynaptic targeting. J Biol Chem. 2012;287:27417–30.

  57. 57.

    Becker JB, Koob GF. Sex differences in animal models: focus on addiction. Pharmacol Rev. 2016;68:242–63.

  58. 58.

    Quadir SG, Guzelian E, Palmer MA, Martin DL, Kim J, Szumlinski KK. Complex interactions between the subject factors of biological sex and prior histories of binge-drinking and unpredictable stress influence behavioral sensitivity to alcohol and alcohol intake. Physiol Behav. 2017:1–24.

  59. 59.

    King AC, de Wit H, McNamara PJ, Cao D. Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking. Arch Gen Psychiatry. 2011;68:389–99.

  60. 60.

    King AC, Hasin D, O’Connor SJ, McNamara PJ, Cao D. A prospective 5-Year re-examination of alcohol response in heavy drinkers progressing in alcohol use disorder. Biol Psychiatry. 2016;79:489–98.

  61. 61.

    King AC, McNamara PJ, Hasin DS, Cao D. Alcohol challenge responses predict future alcohol use disorder symptoms: a 6-year prospective study. Biol Psychiatry. 2014;75:798–806.

  62. 62.

    Roche DJ, Palmeri MD, King AC. Acute alcohol response phenotype in heavy social drinkers is robust and reproducible. Alcohol Clin Exp Res. 2014;38:844–52.

  63. 63.

    Sharko AC, Kaigler KF, Fadel JR, Wilson MA. Ethanol-induced anxiolysis and neuronal activation in the amygdala and bed nucleus of the stria terminalis. Alcohol. 2016;50:19–25.

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Funding

J.M. is supported by the NIH-NINDS grant R01 NS073574 (J.M.). L.C.M. is supported by the NIH-NIGMS grant K12GM074869; an IRACDA postdoctoral training grant to Tufts University (Training in Education and Critical Research Skills: TEACRS). J.T.N., A.St.J. and K.M. were supported by the Tufts University’s Building Diversity in Biomedical Research program. The behavioral and imaging studies were conducted in the Tufts Center for Neuroscience Research, P30 NS047243. J.M. serves on the Scientific Advisory Board for SAGE Therapeutics and receives financial support for research that is unrelated to the current study.

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Competing interests

LCM, JTN, ASJ, and KM report no competing financial interests or conflicts of interest. JLM is a member of the Scientific Advisory Board and consultant for SAGE Therapeutics, a relationship overseen by Tufts University and does not represent a conflict with the current study.

Correspondence to Jamie L. Maguire.

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