Advertisement

Ethanol-induced changes in synaptic amino acid neurotransmitter levels in the nucleus accumbens of differentially sensitized mice

  • Mina G. NashedEmail author
  • Dipashree Chatterjee
  • Diana Nguyen
  • Daria Oleinichenko
  • Mustansir Diwan
  • Jose N. Nobrega
Original Investigation

Abstract

Rationale

Ethanol-induced behavioural sensitization (EBS) does not occur uniformly in mice exposed to the sensitization paradigm. This suggests innate differential responses to ethanol (EtOH) in the reward circuitry of individual animals.

Objectives

To better characterize the adaptive differences between low-sensitized (LS) and high-sensitized (HS) mice, we examined excitatory amino acid (EAA) and inhibitory amino acid (IAA) neurotransmitter levels in the nucleus accumbens (NAc) during EBS expression.

Methods

Male DBA/2J mice received five ethanol (EtOH) (2.2 g/kg) or saline injections, and locomotor activity (LMA) was assessed during EBS induction. EtOH mice were classified as LS or HS on the basis of final LMA scores. Following an EtOH challenge (1.8 g/kg) 2 weeks later, LMA was re-evaluated and in vivo microdialysis samples were collected from the NAc.

Results

Most differences in amino acid levels were observed within the first 20 min after EtOH challenge. LS mice exhibited similar glutamate levels compared with acutely treated (previously EtOH naïve) mice, and generally increased levels of the IAAs GABA, glycine, and taurine. By contrast, HS mice exhibited increased glutamate and attenuated levels of GABA, glycine, and taurine.

Conclusion

These data suggest that the profile of amino acid neurotransmitters in the NAc of LS and HS mice significantly differs. Elucidating these adaptive differences contributes to our understanding of factors that confer susceptibility/resilience to alcohol use disorder.

Keywords

Ethanol Neurotransmitter Nucleus accumbens Alcohol Amino acid Behavioural sensitization Glutamate GABA Glycine Taurine 

Notes

Acknowledgements

The authors thank Dr. Christina Nona and Roger Raymond for excellent technical assistance.

Funding information

This study was supported by NSERC grant RGPIN 06615.

Compliance with ethical standards

All procedures were approved by the Animal Care Committee at the Centre for Addiction and Mental Health and were in accordance with the guidelines and practices outlined by the Canadian Council on Animal Care.

Conflicts of interest

The authors declare that they have no conflicts of interest.

References

  1. Abrahao KP, Quadros IM, Souza-Formigoni ML (2011) Nucleus accumbens dopamine D(1) receptors regulate the expression of ethanol-induced behavioural sensitization. Int J Neuropsychopharmacol 14:175–185.  https://doi.org/10.1017/S1461145710000441 CrossRefGoogle Scholar
  2. Abrahao KP, Quadros IM, Andrade AL, Souza-Formigoni ML (2012) Accumbal dopamine D2 receptor function is associated with individual variability in ethanol behavioral sensitization. Neuropharmacology 62:882–889.  https://doi.org/10.1016/j.neuropharm.2011.09.017 CrossRefGoogle Scholar
  3. Abrahao KP, Ariwodola OJ, Butler TR, Rau AR, Skelly MJ, Carter E, Alexander NP, McCool BA, Souza-Formigoni MLO, Weiner JL (2013) Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration. J Neurosci 33:4834–4842.  https://doi.org/10.1523/JNEUROSCI.5839-11.2013 CrossRefGoogle Scholar
  4. Abrahao KP, Goeldner FO, Souza-Formigoni ML (2014) Individual differences in ethanol locomotor sensitization are associated with dopamine D1 receptor intra-cellular signaling of DARPP-32 in the nucleus accumbens. PLoS One 9:e98296.  https://doi.org/10.1371/journal.pone.0098296 CrossRefGoogle Scholar
  5. Adermark L, Clarke RB, Olsson T, Hansson E, Soderpalm B, Ericson M (2011) Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens. Addict Biol 16:43–54.  https://doi.org/10.1111/j.1369-1600.2010.00206.x CrossRefGoogle Scholar
  6. Broadbent J, Harless WE (1999) Differential effects of GABA(A) and GABA(B) agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2. J Mice Psychopharmacology (Berl) 141:197–205CrossRefGoogle Scholar
  7. Broadbent J, Weitemier AZ (1999) Dizocilpine (MK-801) prevents the development of sensitization to ethanol in DBA/2J mice. Alcohol Alcohol 34:283–288CrossRefGoogle Scholar
  8. Broadbent J, Kampmueller KM, Koonse SA (2003) Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors. Psychopharmacology 167:225–234.  https://doi.org/10.1007/s00213-003-1404-3 CrossRefGoogle Scholar
  9. Camarini R, Frussa-Filho R, Monteiro MG, Calil HM (2000) MK-801 blocks the development of behavioral sensitization to the ethanol. Alcohol Clin Exp Res 24:285–290CrossRefGoogle Scholar
  10. Camarini R, Marcourakis T, Teodorov E, Yonamine M, Calil HM (2011) Ethanol-induced sensitization depends preferentially on D1 rather than D2 dopamine receptors. Pharmacol Biochem Behav 98:173–180.  https://doi.org/10.1016/j.pbb.2010.12.017 CrossRefGoogle Scholar
  11. Carrara-Nascimento PF, Griffin WC 3rd, Pastrello DM, Olive MF, Camarini R (2011) Changes in extracellular levels of glutamate in the nucleus accumbens after ethanol-induced behavioral sensitization in adolescent and adult mice. Alcohol 45:451–460.  https://doi.org/10.1016/j.alcohol.2011.01.002 CrossRefGoogle Scholar
  12. Chatterjee D, Shams S, Gerlai R (2014) Chronic and acute alcohol administration induced neurochemical changes in the brain: comparison of distinct zebrafish populations. Amino Acids 46:921–930.  https://doi.org/10.1007/s00726-013-1658-y CrossRefGoogle Scholar
  13. Clapp PF, Bhave SF, Hoffman PL (2018) How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health 31:310–339Google Scholar
  14. Crabbe JC Jr, Johnson NA, Gray DK, Kosobud A, Young ER (1982) Biphasic effects of ethanol on open-field activity: sensitivity and tolerance in C57BL/6N and DBA/2N mice. J Comp Physiol Psychol 96:440–451CrossRefGoogle Scholar
  15. Dahchour A, De Witte P (2000) Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 60:343–362CrossRefGoogle Scholar
  16. Dahchour A, Quertemont E, Dewitte P (1994) Acute ethanol increases taurine but neither glutamate nor Gaba in the nucleus-accumbens of male-rats a microdialysis study. Alcohol Alcohol 29:485–487Google Scholar
  17. Dahchour A, Quertemont E, De Witte P (1996) Taurine increases in the nucleus accumbens microdialysate after acute ethanol administration to naive and chronically alcoholised rats. Brain Res 735:9–19CrossRefGoogle Scholar
  18. Dahchour A, Hoffman A, Deitrich R, de Witte P (2000) Effects of ethanol on extracellular amino acid levels in high-and low-alcohol sensitive rats: a microdialysis study. Alcohol Alcohol 35:548–553CrossRefGoogle Scholar
  19. DeVos SL et al (2013) Antisense reduction of tau in adult mice protects against seizures. J Neurosci 33:12887–12897.  https://doi.org/10.1523/JNEUROSCI.2107-13.2013 CrossRefGoogle Scholar
  20. Ding ZM, Ingraham CM, Rodd ZA, McBride WJ (2015) The reinforcing effects of ethanol within the nucleus accumbens shell involve activation of local GABA and serotonin receptors. J Psychopharmacol 29:725–733.  https://doi.org/10.1177/0269881115581982 CrossRefGoogle Scholar
  21. Ericson M, Ulenius L, Adermark L, Soderpalm B (2017) Minor adaptations of ethanol-induced release of taurine following chronic ethanol intake in the rat. Adv Exp Med Biol 975(Pt 1):217–224.  https://doi.org/10.1007/978-94-024-1079-2_19 CrossRefGoogle Scholar
  22. Ferrario CR, Robinson TE (2007) Amphetamine pretreatment accelerates the subsequent escalation of cocaine self-administration behavior. Eur Neuropsychopharmacol 17:352–357.  https://doi.org/10.1016/j.euroneuro.2006.08.005 CrossRefGoogle Scholar
  23. Fidler TL, Dion AM, Powers MS, Ramirez JJ, Mulgrew JA, Smitasin PJ, Crane AT, Cunningham CL (2011) Intragastric self-infusion of ethanol in high- and low-drinking mouse genotypes after passive ethanol exposure. Genes Brain Behav 10:264–275.  https://doi.org/10.1111/j.1601-183X.2010.00664.x CrossRefGoogle Scholar
  24. Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  25. Griffin WC, Ramachandra VS, Knackstedt LA, Becker HC (2015) Repeated cycles of chronic intermittent ethanol exposure increases basal glutamate in the nucleus accumbens of mice without affecting glutamate transport. Front Pharmacol 6:27.  https://doi.org/10.3389/fphar.2015.00027 CrossRefGoogle Scholar
  26. Gulya K, Grant KA, Valverius P, Hoffman PL, Tabakoff B (1991) Brain regional specificity and time-course of changes in the NMDA receptor-ionophore complex during ethanol withdrawal. Brain Res 547:129–134CrossRefGoogle Scholar
  27. Harrison SJ, Nobrega JN (2009) Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice. Psychopharmacology 204:49–59.  https://doi.org/10.1007/s00213-008-1435-x CrossRefGoogle Scholar
  28. Harvey RJ, Yee BK (2013) Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov 12:866–885.  https://doi.org/10.1038/nrd3893 CrossRefGoogle Scholar
  29. Herring BE, Silm K, Edwards RH, Nicoll RA (2015) Is aspartate an excitatory neurotransmitter? J Neurosci 35:10168–10171.  https://doi.org/10.1523/JNEUROSCI.0524-15.2015 CrossRefGoogle Scholar
  30. Hitzemann B, Hitzemann R (1997) Genetics ethanol and the Fos response: a comparison of the C57BL/6J and DBA/2J inbred mouse strains. Alcohol Clin Exp Res 21:1497–1507Google Scholar
  31. Holmes A, Spanagel R, Krystal JH (2013) Glutamatergic targets for new alcohol medications. Psychopharmacology 229:539–554.  https://doi.org/10.1007/s00213-013-3226-2 CrossRefGoogle Scholar
  32. Hu XJ, Ticku MK (1995) Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons. Brain Res Mol Brain Res 30:347–356CrossRefGoogle Scholar
  33. Juarez B, Morel C, Ku SM, Liu Y, Zhang H, Montgomery S, Gregoire H, Ribeiro E, Crumiller M, Roman-Ortiz C, Walsh JJ, Jackson K, Croote DE, Zhu Y, Zhang S, Vendruscolo LF, Edwards S, Roberts A, Hodes GE, Lu Y, Calipari ES, Chaudhury D, Friedman AK, Han MH (2017) Midbrain circuit regulation of individual alcohol drinking behaviors in mice. Nat Commun 8:2220.  https://doi.org/10.1038/s41467-017-02365-8 CrossRefGoogle Scholar
  34. Kai N, Nishizawa K, Tsutsui Y, Ueda S, Kobayashi K (2015) Differential roles of dopamine D1 and D2 receptor-containing neurons of the nucleus accumbens shell in behavioral sensitization. J Neurochem 135:1232–1241.  https://doi.org/10.1111/jnc.13380 CrossRefGoogle Scholar
  35. Kalivas PW (1995) Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants. Drug Alcohol Depend 37:95–100CrossRefGoogle Scholar
  36. Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16:223–244CrossRefGoogle Scholar
  37. Koob GF (2004) A role for GABA mechanisms in the motivational effects of alcohol. Biochem Pharmacol 68:1515–1525.  https://doi.org/10.1016/j.bcp.2004.07.031 CrossRefGoogle Scholar
  38. Kruse LC, Linsenbardt DN, Boehm SL 2nd (2012) Positive allosteric modulation of the GABA(B) receptor by GS39783 attenuates the locomotor stimulant actions of ethanol and potentiates the induction of locomotor sensitization. Alcohol 46:455–462.  https://doi.org/10.1016/j.alcohol.2012.03.004 CrossRefGoogle Scholar
  39. Krystal JH, Petrakis IL, Krupitsky E, Schutz C, Trevisan L, D'Souza DC (2003) NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy. Ann N Y Acad Sci 1003:176–184CrossRefGoogle Scholar
  40. Leyton M (2007) Conditioned and sensitized responses to stimulant drugs in humans. Prog Neuro-Psychopharmacol Biol Psychiatry 31:1601–1613.  https://doi.org/10.1016/j.pnpbp.2007.08.027 CrossRefGoogle Scholar
  41. Li Z, Zharikova A, Bastian J, Esperon L, Hebert N, Mathes C, Rowland NE, Peris J (2008) High temporal resolution of amino acid levels in rat nucleus accumbens during operant ethanol self-administration: involvement of elevated glycine in anticipation. J Neurochem 106:170–181.  https://doi.org/10.1111/j.1471-4159.2008.05346.x CrossRefGoogle Scholar
  42. Li YL, Liu Q, Gong Q, Li JX, Wei SP, Wang YT, Liang H, Zhang M, Jing L, Yong Z, Lawrence AJ, Liang JH (2014) Brucine suppresses ethanol intake and preference in alcohol-preferring fawn-hooded rats. Acta Pharmacol Sin 35:853–861.  https://doi.org/10.1038/aps.2014.28 CrossRefGoogle Scholar
  43. Linsenbardt DN, Boehm SL 2nd (2010) Ethanol-induced locomotor sensitization in DBA/2J mice is associated with alterations in GABA(A) subunit gene expression and behavioral sensitivity to GABA(A) acting drugs. Pharmacol Biochem Behav 95:359–366.  https://doi.org/10.1016/j.pbb.2010.02.014 CrossRefGoogle Scholar
  44. Lobo IA, Harris RA (2008) GABA(A) receptors and alcohol. Pharmacol Biochem Behav 90:90–94.  https://doi.org/10.1016/j.pbb.2008.03.006 CrossRefGoogle Scholar
  45. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science (New York, NY) 243:1721–1724CrossRefGoogle Scholar
  46. McCool BA, Chappell AM (2014) Persistent enhancement of ethanol drinking following a monosodium glutamate-substitution procedure in C57BL6/J and DBA/2J mice. Alcohol 48:55–61.  https://doi.org/10.1016/j.alcohol.2013.10.008 CrossRefGoogle Scholar
  47. Melendez RI, HM P, CS S, Kalivas PW (2005) Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcohol Clin Exp Res 29:326–333CrossRefGoogle Scholar
  48. Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL (1997) Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature 389:385–389.  https://doi.org/10.1038/38738 CrossRefGoogle Scholar
  49. Miladinovic T, Nashed MG, Singh G (2015) Overview of glutamatergic dysregulation in central pathologies. Biomolecules 5:3112–3141.  https://doi.org/10.3390/biom5043112 CrossRefGoogle Scholar
  50. Molander A, Soderpalm B (2005) Accumbal strychnine-sensitive glycine receptors: an access point for ethanol to the brain reward system. Alcohol Clin Exp Res 29:27–37CrossRefGoogle Scholar
  51. Molander A, Lof E, Stomberg R, Ericson M, Soderpalm B (2005) Involvement of accumbal glycine receptors in the regulation of voluntary ethanol intake in the rat. Alcohol Clin Exp Res 29:38–45CrossRefGoogle Scholar
  52. Nona CN, Nobrega JN (2018) A role for nucleus accumbens glutamate in the expression but not the induction of behavioural sensitization to ethanol. Behav Brain Res 336:269–281.  https://doi.org/10.1016/j.bbr.2017.09.024 CrossRefGoogle Scholar
  53. Nona CN, Guirguis S, Nobrega JN (2013) Susceptibility to ethanol sensitization is differentially associated with changes in pCREB, trkB and BDNF mRNA expression in the mouse brain. Behav Brain Res 242:25–33.  https://doi.org/10.1016/j.bbr.2012.12.035 CrossRefGoogle Scholar
  54. Nona CN, Li R, Nobrega JN (2014) Altered NMDA receptor subunit gene expression in brains of mice showing high vs. low sensitization to ethanol. Behav Brain Res 260:58–66.  https://doi.org/10.1016/j.bbr.2013.11.037 CrossRefGoogle Scholar
  55. Nona CN, Creed MC, Hamani C, Nobrega JN (2015) Effects of high-frequency stimulation of the nucleus accumbens on the development and expression of ethanol sensitization in mice. Behav Pharmacol 26:184–192.  https://doi.org/10.1097/FBP.0000000000000033 CrossRefGoogle Scholar
  56. Nona CN, Lam M, Nobrega JN (2016) Localized brain differences in arc expression between mice showing low vs. high propensity to ethanol sensitization. Pharmacol Biochem Behav 142:15–22.  https://doi.org/10.1016/j.pbb.2015.12.006 CrossRefGoogle Scholar
  57. Roberto M, Madamba SG, Stouffer DG, Parsons LH, Siggins GR (2004) Increased GABA release in the central amygdala of ethanol-dependent rats. J Neurosci 24:10159–10166.  https://doi.org/10.1523/JNEUROSCI.3004-04.2004 CrossRefGoogle Scholar
  58. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291CrossRefGoogle Scholar
  59. Robinson TE, Berridge KC (2008) Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond Ser B Biol Sci 363:3137–3146.  https://doi.org/10.1098/rstb.2008.0093 CrossRefGoogle Scholar
  60. Rossetti ZL, Carboni S (1995) Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum. Eur J Pharmacol 283:177–183.  https://doi.org/10.1016/0014-2999(95)00344-K CrossRefGoogle Scholar
  61. Segal DS, Mandell AJ (1974) Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav 2:249–255CrossRefGoogle Scholar
  62. Smith A, Watson CJ, Frantz KJ, Eppler B, Kennedy RT, Peris J (2004) Differential increase in taurine levels by low-dose ethanol in the dorsal and ventral striatum revealed by microdialysis with on-line capillary electrophoresis. Alcohol Clin Exp Res 28:1028–1038CrossRefGoogle Scholar
  63. Souza-Formigoni MLO, De Lucca EM, Hipolide DC, Enns SC, Oliveira MGM, Nobrega JN (1999) Sensitization to ethanol's stimulant effect is associated with region-specific increases in brain D2 receptor binding. Psychopharmacology 146:262–267.  https://doi.org/10.1007/s002130051115 CrossRefGoogle Scholar
  64. Tran AH, Tamura R, Uwano T, Kobayashi T, Katsuki M, Ono T (2005) Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place. Proc Natl Acad Sci U S A 102:2117–2122.  https://doi.org/10.1073/pnas.0409726102 CrossRefGoogle Scholar
  65. Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT (1998) Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry 155:726–732.  https://doi.org/10.1176/ajp.155.6.726 CrossRefGoogle Scholar
  66. Tzschentke TM, Schmidt WJ (2003) Glutamatergic mechanisms in addiction. Mol Psychiatry 8:373–382.  https://doi.org/10.1038/sj.mp.4001269 CrossRefGoogle Scholar
  67. Ulrich JD, Burchett JM, Restivo JL, Schuler DR, Verghese PB, Mahan TE, Landreth GE, Castellano JM, Jiang H, Cirrito JR, Holtzman DM (2013) In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener 8:13.  https://doi.org/10.1186/1750-1326-8-13 CrossRefGoogle Scholar
  68. Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, Adams LJ, Vengeliene V, Spanagel R, Zhang Y, Shen J, George DT, Hommer D, Heilig M (2010) Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67:1069–1077.  https://doi.org/10.1001/archgenpsychiatry.2010.125 CrossRefGoogle Scholar
  69. Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120CrossRefGoogle Scholar
  70. Vengeliene V, Leonardi-Essmann F, Sommer WH, Marston HM, Spanagel R (2010) Glycine transporter-1 blockade leads to persistently reduced relapse-like alcohol drinking in rats. Biol Psychiatry 68:704–711.  https://doi.org/10.1016/j.biopsych.2010.05.029 CrossRefGoogle Scholar
  71. Vezina P, Leyton M (2009) Conditioned cues and the expression of stimulant sensitization in animals and humans. Neuropharmacology 56(Suppl 1):160–168.  https://doi.org/10.1016/j.neuropharm.2008.06.070 CrossRefGoogle Scholar
  72. Weiner JL, Valenzuela CF (2006) Ethanol modulation of GABAergic transmission: the view from the slice. Pharmacol Ther 111:533–554.  https://doi.org/10.1016/j.pharmthera.2005.11.002 CrossRefGoogle Scholar
  73. Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720CrossRefGoogle Scholar
  74. Xie R, Hammarlund-Udenaes M - de Boer AG, de Boer AG de Lange EC, de Lange EC (1999) The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice Br J Pharmacol 128:563–568CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Behavioural Neurobiology Laboratory, Research Imaging CentreCentre for Addiction and Mental HealthTorontoCanada
  2. 2.Departments of PsychologyUniversity of TorontoTorontoCanada
  3. 3.Departments of PsychiatryUniversity of TorontoTorontoCanada
  4. 4.Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
  5. 5.Campbell Family Mental Health Research InstituteCentre for Addiction and Mental HealthTorontoCanada

Personalised recommendations