Advertisement

α5GABAA subunit-containing receptors and sweetened alcohol cue-induced reinstatement and active sweetened alcohol self-administration in male rats

  • Cassie M. Chandler
  • Jaren Reeves-Darby
  • Sherman A. Jones
  • J. Abigail McDonald
  • Guanguan Li
  • Md T. Rahman
  • James M. Cook
  • Donna M. Platt
Original Investigation
  • 15 Downloads

Abstract

Rationale

GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) appear to be critically involved in the reinforcing and subjective effects of alcohol. Their role in alcohol relapse remains unknown.

Objectives

Pharmacological approaches were used to probe the role of α5GABAA receptors in alcohol seeking induced by re-exposure to a sweetened alcohol-paired cue, as well as in alcohol + sucrose vs. sucrose self-administration.

Methods

For reinstatement studies, rats were trained to self-administer alcohol under a fixed-ratio schedule in which responding was maintained by alcohol + sucrose deliveries and an alcohol-paired stimulus. Sweetened alcohol seeking was extinguished by eliminating solution deliveries and the sweetened alcohol-paired stimulus. During reinstatement tests, animals received pretreatments of an α5GABAA inverse agonist (L-655,708) or an agonist (QH-ii-066) prior to sessions in which presentation of the sweetened alcohol-paired stimulus was restored, but no solution was delivered. For self-administration studies, rats were trained to self-administer alcohol + sucrose or sucrose under a fixed-ratio schedule. Once stable, animals received pretreatments of QH-ii-066, L-655,708, the inverse agonist RY-023, or naltrexone.

Results

L-655,708 attenuated reinstatement of sweetened alcohol seeking by alcohol + sucrose-paired cues; whereas sweetened alcohol-seeking behavior was augmented by QH-ii-066, albeit at different doses in different rats. Both L-655,708 and RY-023 selectively reduced alcohol + sucrose vs. sucrose self-administration. In contrast, naltrexone reduced both alcohol + sucrose and sucrose self-administration; whereas QH-ii-066 enhanced sucrose self-administration only.

Conclusions

α5GABAA receptors play a key role in the modulation of sweetened alcohol cue-induced reinstatement, as well as in alcohol + sucrose but not sucrose self-administration. Inverse agonist activity at α5GABAA receptors may offer a novel strategy for both the reduction of problematic drinking and the prevention of relapse.

Keywords

Alcohol Ethanol Reinstatement Self-administration GABAA receptors 

Notes

Acknowledgements

We would like to thank Dr. Joyce Besheer (UNC-Chapel Hill) for invaluable advice regarding alcohol self-administration in rats; Dr. Kevin Freeman (UMMC) for use of his operant conditioning chambers, and Dr. Sally Huskinson for her Med State programming expertise. We also would like to thank the Shimadzu Analytical Laboratory of Southeastern Wisconsin.

Compliance with ethical standards

All animals were maintained and experiments were conducted in accordance with the University of Mississippi Medical Center’s Institutional Animal Care and Use Committee and were in accordance with the National Research Council’s Guide for Care and Use of Laboratory Animals (eighth edition, 2011).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Amaral DG, Witter MP (1989) The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31:571–591CrossRefGoogle Scholar
  2. Atack JR (2010) Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA. Pharmacol Ther 125:11–26CrossRefGoogle Scholar
  3. Atack JR, Bayley PJ, Seabrook GR, Wafford KA, McKernan RM, Dawson GR (2006) L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. Neuropharmacology 51:1023–1029CrossRefGoogle Scholar
  4. Backstrom P, Bachteler D, Koch S, Hyytia P, Spanagel R (2004) mGluR5 antagonist MPEP reduces ethanol seeking and relapse behavior. Neuropsychopharmacology 29:921–928CrossRefGoogle Scholar
  5. Besheer J, Faccidomo S, Grondin JJ, Hodge CW (2008) Regulation of motivation to self-administer ethanol by mGluR5 in alcohol-preferring (P) rats. Alcohol Clin Exp Res 32:209–221CrossRefGoogle Scholar
  6. Besheer J, Fisher KR, Lindsay TG, Cannady R (2013) Transient increase in alcohol self-administration following a period of chronic exposure to corticosterone. Neuropharmacology 72:139–147CrossRefGoogle Scholar
  7. Boehm SL 2nd, Ponomarev I, Jennings AW, Whiting PJ, Rosahl TW, Garrett EM, Blednov YA, Harris RA (2004) Gamma-aminobutyric acid a receptor subunit mutant mice: new perspectives on alcohol actions. Biochem Pharmacol 68:1581–1602CrossRefGoogle Scholar
  8. Cannady R, Fisher KR, Durant B, Besheer J, Hodge CW (2013) Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addict Biol 18:54–65CrossRefGoogle Scholar
  9. Casula MA, Bromidge FA, Pillai GV, Wingrove PB, Martin K, Maubach K, Seabrook GR, Whiting PJ, Hadingham KL (2001) Identification of amino acid residues responsible for the alpha-5 subunit binding selectivity of L-655,708, a benzodiazepine binding site ligand at the GABA-A receptor. J Neurochem 77:445–451CrossRefGoogle Scholar
  10. Charlton ME, Sweetnam PM, Fitzgerald LW, Terwilliger RZ, Nestler EJ, Duman RS (1997) Chronic ethanol administration regulates the expression of GABAA receptor alpha 1 and alpha 5 subunits in the ventral tegmental area and hippocampus. J Neurochem 68:121–127CrossRefGoogle Scholar
  11. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci 22:5572–5580CrossRefGoogle Scholar
  12. Cook JB, Foster KL, Eiler WJ 2nd, McKay PF, Woods J 2nd, Harvey SC, Garcia M, Grey C, McCane S, Mason D, Cummings R, Li X, Cook JM, June HL (2005) Selective GABAA alpha5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol. Alcohol Clin Exp Res 29:1390–1401CrossRefGoogle Scholar
  13. den Uyl TE, Gladwin TE, Wiers RW (2016) Electrophysiological and behavioral effects of combined transcranial direct current stimulation and alcohol approach bias retraining in hazardous drinkers. Alcohol Clin Exp Ther 40:2124–2133CrossRefGoogle Scholar
  14. Fritschy JM, Panzanelli P (2014) GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system. Eur J Neurosci 39:1845–1865CrossRefGoogle Scholar
  15. Gatto GJ, Grant KA (1997) Attenuation of the discriminative stimulus effects of ethanol by the benzodiazepine partial inverse agonist Ro 15-4513. Behav Pharmacol 8:139–146PubMedGoogle Scholar
  16. Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS (2017) Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: results from the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry 74:911–923CrossRefGoogle Scholar
  17. Groenewegen HJ, Vermeulen-Van der Zee E, te Kortschot A, Witter MP (1987) Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 23:103–120CrossRefGoogle Scholar
  18. Hamel L, Thangarasa T, Samadi O, Ito R (2017) Caudal nucleus accumbens core is critical in the regulation of cue-elicited approach-avoidance decisions. eNeuro 4:ENEURO.0330–ENEU16.2017.  https://doi.org/10.1523/ENEURO.0330-16.2017 CrossRefGoogle Scholar
  19. Hay RA, Jennings JH, Zitzman DL, Hodge CW, Robinson DL (2013) Specific and nonspecific effects of naltrexone on goal-directed and habitual models of alcohol seeking and drinking. Alcohol Clin Exp Res 37:1100–1110CrossRefGoogle Scholar
  20. Helms CM, Rogers LS, Grant KA (2009) Antagonism of the ethanol-like discriminative stimulus effects of ethanol, pentobarbital, and midazolam in cynomolgus monkeys reveals involvement of specific GABAA receptor subtypes. J Pharmacol Exp Ther 331:142–152CrossRefGoogle Scholar
  21. Hodges LM, Fyer AJ, Weissman MM, Logue MW, Haghighi F, Evgrafov O, Rotondo A, Knowles JA, Hamilton SP (2014) Evidence for linkage and association of GABRB3 and GABRA5 to panic disorder. Neuropsychopharmacology 39:2423–2431CrossRefGoogle Scholar
  22. Howell O, Atack JR, Dewar D, McKernan RM, Sur C (2000) Density and pharmacology of alpha5 subunit-containing GABAA receptors are preserved in hippocampus of Alzheimer's disease patients. Neuroscience 98:669–675CrossRefGoogle Scholar
  23. Huang Q, He X, Ma C, Liu R, Yu S, Dayer CA, Wenger GR, McKernan R, Cook JM (2000) Pharmacophore/receptor models for GABAA/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach. J Med Chem 43:71–95CrossRefGoogle Scholar
  24. Huang Q, Zhang W, Liu R, McKernan RM, Cook JM (1996) Benzo-fused benzodiazepines as topological probes for the study of benzodiazepine receptor subtypes. Med Chem Res 6:384–391Google Scholar
  25. Janak PH, Chaudhri N (2010) The potent effect of environmental context on relapse to alcohol-seeking after extinction. Open Addict J 3:76–87CrossRefGoogle Scholar
  26. Jin Z, Bazov I, Kononenko O, Korpi ER, Bakalkin G, Birnir B (2012) Selective changes of GABAA channel subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics. Front Cell Neurosci 5:30.  https://doi.org/10.3389/fncel.2011.00030
  27. June HL, Harvey SC, Foster KL, McKay PF, Cummings R, Garcia M, Mason D, Grey C, McCane S, Williams LS, Johnson TB, He X, Rock S, Cook JM (2001) GABAA receptors containing α5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry. J Neurosci 21:2166–2177CrossRefGoogle Scholar
  28. Kelley AE, Domesick VB (1982) The distribution of the projection from the hippocampal formation to the nucleus accumbens in the rat: an anterograde- and retrograde-horseradish peroxidase study. Neuroscience 7:2321–2335CrossRefGoogle Scholar
  29. Knust H, Achermann G, Ballard T, Buettelmann B, Gasser R, Fischer H, Hernandez MC, Knoflach F, Koblet A, Stadler H, Thomas AW, Trube G, Waldmeier P (2009) The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction. Bioorg Med Chem Lett 19:5940–5944CrossRefGoogle Scholar
  30. Langleben DD, Busch EL, O'Brien CP, Elman I (2012) Depot naltrexone decreases rewarding properties of sugar in patients with opioid dependence. Psychopharmacology 220:559–564CrossRefGoogle Scholar
  31. Li M, Szabo A, Rosenberg HC (2001) Evaluation of native GABAA receptors containing an alpha 5 subunit. Eur J Pharmacol 413:63–72CrossRefGoogle Scholar
  32. Liu R, Hu RJ, Zhang P, Skolnick P, Cook JM (1996) Synthesis and pharmacological properties of novel 8-substituted imidazobenzodiazepines: high-affinity, selective probes for alpha 5-containing GABAA receptors. J Med Chem 39:1928–1934CrossRefGoogle Scholar
  33. López-León S, Janssens ACJW, González-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA, van Duijn CM (2008) Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry 13:772–785CrossRefGoogle Scholar
  34. Luo AH, Tahsili-Fahadan P, Wise RA, Lupica CR, Aston-Jones G (2011) Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science 333:353–357CrossRefGoogle Scholar
  35. McKay PF, Foster KL, Mason D, Cummings R, Garcia M, Williams LS, Grey C, McCane S, He X, Cook JM, June HL (2004) A high affinity ligand for GABAA-receptor containing alpha5 subunit antagonizes ethanol’s neurobehavioral effects in Long-Evans rats. Psychopharmacology 172:455–462CrossRefGoogle Scholar
  36. McKernan RM, Whiting PJ (1996) Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci 19:139–143CrossRefGoogle Scholar
  37. Middaugh LD, Bao K, Becker HC, Daniel SS (1991) Effects of Ro 15-4513 on ethanol discrimination in C57BL/6 mice. Pharmacol Biochem Behav 38:763–767CrossRefGoogle Scholar
  38. Möhler H, Rudolph U (2017) Disinhibition, an emerging pharmacology of learning and memory. F1000Res.  https://doi.org/10.12688/f1000research.9947.1
  39. Navarro JF, Burón E, Martín-López M (2002) Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test. Prog Neuro-Psychopharmacol Biol Psychiatry 26:1389–1392CrossRefGoogle Scholar
  40. Nguyen D, Schumacher A, Erb S, Ito R (2015) Aberrant approach-avoidance conflict resolution following repeated cocaine pre-exposure. Psychopharmacology 232:3573–3583CrossRefGoogle Scholar
  41. Otani K, Ujike H, Tanaka Y, Morita Y, Katsu T, Nomura A, Uchida N, Hamamura T, Fujiwara Y, Kuroda S (2005) The GABA type a receptor α5 subunit gene is associated with bipolar I disorder. Neurosci Lett 381:10–17CrossRefGoogle Scholar
  42. Platt DM, Duggan A, Spealman RD, Cook JM, Li X, Yin W, Rowlett JK (2005) Contribution of α1GABAA and α5GABAA receptor subtypes to the discriminative stimulus effects of ethanol in squirrel monkeys. J Pharmacol Exp Ther 313:658–667CrossRefGoogle Scholar
  43. Pofantis H, Papatheodoropoulos C (2014) The α5GABAA receptor modulates the induction of long-term potentiation at ventral but not dorsal CA1 hippocampal synapses. Synapse 68:394–401CrossRefGoogle Scholar
  44. Prut L, Prenosil G, Willadt S, Vogt K, Fritschy JM, Crestani F (2010) A reduction in hippocampal GABAA receptor alpha5 subunits disrupts the memory for location of objects in mice. Genes Brain Behav 9:478–488PubMedGoogle Scholar
  45. Redrobe JP, Elster L, Frederiksen K, Bundgaard C, de Jong IE, Smith GP, Bruun AT, Larsen PH, Didriksen M (2012) Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats. Psychopharmacology 221:451–468CrossRefGoogle Scholar
  46. Rees DC, Balster RL (1988) Attenuation of the discriminative stimulus properties of ethanol and oxazepam, but not of pentobarbital, by Ro 15-4513 in mice. J Pharmacol Exp Ther 244:592–598PubMedGoogle Scholar
  47. Rehm J, Mathers C, Popova S, Thavomcharoensap M, Teerawattananon Y, Patra J (2009) Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373:2223–2233CrossRefGoogle Scholar
  48. Rudolph U, Möhler H (2004) Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol 44:475–498CrossRefGoogle Scholar
  49. Rüedi-Bettschen D, Rowlett JK, Rallapalli S, Clayton T, Cook JM, Platt DM (2013) Modulation of α5 subunit-containing GABAA receptors alters alcohol drinking by rhesus monkeys. Alcohol Clin Exp Res 37:624–634CrossRefGoogle Scholar
  50. Samson HH (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 10:436–442CrossRefGoogle Scholar
  51. Sarantis K, Sotiriou E, Papatheodoropoulos C, Matsokis N, Angelatou F (2008) Differential pharmacological properties of GABAA/benzodiazepine receptor complex in dorsal compared to ventral rat hippocampus. Neurochem Int 52:1019–1029CrossRefGoogle Scholar
  52. Schumacher A, Villaruel FR, Ussling A, Riaz S, Lee ACH, Ito R (2018) Ventral hippocampal CA1 and CA3 differentially mediate learned approach-avoidance conflict processing. Curr Biol 28:1318–1324.e4.  https://doi.org/10.1016/j.cub.2018.03.012 CrossRefPubMedGoogle Scholar
  53. Sesack SR, Grace AA (2010) Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35:27–47CrossRefGoogle Scholar
  54. Shelton KL, Grant KA (2001) Effects of naltrexone and Ro 15-4513 on a multiple schedule of ethanol and Tang self-administration. Alcohol Clin Exp Res 25:1576–1585CrossRefGoogle Scholar
  55. Song J, Koller DL, Foroud T, Carr K, Zhao J, Rice J, Nurnberger JI Jr, Begleiter H, Porjesz B, Smith TL, Schuckit MA, Edenberg HJ (2003) Association of GABAA receptors and alcohol dependence and the effects of genetic imprinting. Am J Med Genet B Neuropsychiatr Genet 117B:39–45CrossRefGoogle Scholar
  56. Sur C, Fresu L, Howell O, McKernan RM, Atack JR (1999) Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain. Brain Res 822:265–270CrossRefGoogle Scholar
  57. Uusi-Oukari M, Korpi ER (2010) Regulation of GABAA receptor subunit expression by pharmacological agents. Pharmacol Rev 62:97–135CrossRefGoogle Scholar
  58. Weiss F (2010) Advances in animal models of relapse for addiction research. In: Kuhn CM, Koob GF (eds) Advances in the neuroscience of addiction, 2nd edn. CRC Press/Taylor & Francis, Boca Raton Chapter 1Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Graduate Program in NeuroscienceUniversity of Mississippi Medical CenterJacksonUSA
  2. 2.Department of Psychiatry & Human BehaviorUniversity of Mississippi Medical CenterJacksonUSA
  3. 3.Department of Chemistry & BiochemistryUniversity of Wisconsin-MilwaukeeMilwaukeeUSA

Personalised recommendations