Abstract
Studies have demonstrated that deletion of equilibrative nucleoside transporter 1 (ENT1) is associated with reduced glutamate transporter 1 (GLT1) level, and consequently increased ethanol intake. In this study, we measured changes in GLT1 and ENT1 levels in prefrontal cortex (PFC), and nucleus accumbens (NAc) core and shell associated with alcohol drinking in alcohol-preferring (P) rats. We examined, then, whether ceftriaxone (CEF) would affect both GLT1 and ENT1 levels in these brain regions. P rats were given 24-h concurrent access to 15 and 30 % ethanol, water, and food for 5 weeks. On Week 6, P rats received 100 mg/kg CEF (i.p.) or a saline vehicle for five consecutive days. Ethanol intake was measured daily for 8 days starting on the first day of injections. We found a significant reduction in daily ethanol intake in CEF-treated group, starting on Day 2 of injections. Western blot for GLT1 and binding assay for ENT1 revealed downregulation of GLT1 level, whereas ENT1 levels were increased in the NAc core and NAc shell, respectively, but not in the PFC in saline vehicle group. Importantly, CEF treatment reversed these effects in both NAc core and shell. These findings provide evidence for potential regulatory effects of CEF on both GLT1 and ENT1 expression in reducing ethanol intake.
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References
Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28:309–369
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18
Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, Diamond I, Bonci A, Messing RO (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci 7:855–861
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
Ginsberg SD, Martin LJ, Rothstein JD (1995) Regional deafferentation down-regulates subtypes of glutamate transporter proteins. J Neurochem 65:2800–2803
Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159:1642–1652
Harvey J, Lacey MG (1997) A postsynaptic interaction between dopamine D1 and NMDA receptors promotes presynaptic inhibition in the rat nucleus accumbens via adenosine release. J Neurosci 17:5271–5280
Kalivas PW (2004) Glutamate systems in cocaine addiction. Curr Opin Pharmacol 4:23–29
Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC, Stebbins JL, Pellecchia M, Sarkar D, Fisher PB (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226:2484–2493
Knackstedt LA, Melendez RI, Kalivas PW (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67:81–84
Krystal JH, Petrakis IL, Mason G, Trevisan L, D'Souza DC (2003) N-Methyl-d-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol Ther 99:79–94
Melendez RI, Hicks MP, Cagle SS, Kalivas PW (2005) Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcohol Clin Exp Res 29:326–333
Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR, Kennedy RT, Rebec GV (2008) Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse. Neuroscience 153:329–337
Mitani A, Tanaka K (2003) Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1. J Neurosci 23:7176–7182
Nam HW, Lee MR, Zhu Y, Wu J, Hinton DJ, Choi S, Kim T, Hammack N, Yin JC, Choi DS (2011) Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-d-aspartate receptor signaling. Biol Psychiatry 69:1043–1051
Nam HW, McIver SR, Hinton DJ, Thakkar MM, Sari Y, Parkinson FE, Haydon PG, Choi DS (2012) Adenosine and glutamate signaling in neuron–glial interactions: implications in alcoholism and sleep disorders. Alcohol Clin Exp Res 36:1117–1125
Othman T, Sinclair CJ, Haughey N, Geiger JD, Parkinson FE (2002) Ethanol alters glutamate but not adenosine uptake in rat astrocytes: evidence for protein kinase C involvement. Neurochem Res 27:289–296
Parkinson FE, Xiong W, Zamzow CR, Chestley T, Mizuno T, Duckworth ML (2009) Transgenic expression of human equilibrative nucleoside transporter 1 in mouse neurons. J Neurochem 109:562–572
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic, New York
Qrunfleh AM, Alazizi A, Sari Y (2013) Ceftriaxone, a beta-lactam antibiotic, attenuates relapse-like ethanol-drinking behavior in alcohol-preferring rats. J Psychopharmacol 27:541–549
Rothstein JD (1995) Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis. Clin Neurosci 3:348–359
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84
Sari Y, Franklin KM, Alazizi A, Rao PS, Bell RL (2013) Effects of ceftriaxone on the acquisition and maintenance of ethanol drinking in peri-adolescent and adult female alcohol-preferring (P) rats. Neuroscience 241:229–238
Sari Y, Prieto AL, Barton SJ, Miller BR, Rebec GV (2010) Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington's disease. J Biomed Sci 17:62
Sari Y, Sakai M, Weedman JM, Rebec GV, Bell RL (2011) Ceftriaxone, a beta-lactam antibiotic, reduces ethanol consumption in alcohol-preferring rats. Alcohol Alcohol 46:239–246
Sari Y, Smith KD, Ali PK, Rebec GV (2009) Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J Neurosci 29:9239–9243
Sari Y, Sreemantula SN (2012) Neuroimmunophilin GPI-1046 reduces ethanol consumption in part through activation of GLT1 in alcohol-preferring rats. Neuroscience 227C:327–335
Schreiber R, Freund WD (2000) Glutamate transport is downregulated in the cerebral cortex of alcohol-preferring rats. Med Sci Monit 6:649–652
Smith AD, Weiss F (1999) Ethanol exposure differentially alters central monoamine neurotransmission in alcohol-preferring versus -nonpreferring rats. J Pharmacol Exp Ther 288:1223–1228
Smith TL (1997) Regulation of glutamate uptake in astrocytes continuously exposed to ethanol. Life Sci 61:2499–2505
Wu J, Lee MR, Choi S, Kim T, Choi DS (2010) ENT1 regulates ethanol-sensitive EAAT2 expression and function in astrocytes. Alcohol Clin Exp Res 34:1110–1117
Wu J, Lee MR, Kim T, Johng S, Rohrback S, Kang N, Choi DS (2011) Regulation of ethanol-sensitive EAAT2 expression through adenosine A1 receptor in astrocytes. Biochem Biophys Res Commun 406:47–52
Acknowledgments
This work was supported by Award Number R01AA019458 (Y.S.) and R01AA018779 (D-S. C.) from the National Institutes on Alcohol Abuse and Alcoholism. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism or the National Institutes of Health. The authors would like to thank Mrs. Charisse Montgomery for editing this manuscript.
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Sari, Y., Sreemantula, S.N., Lee, M.R. et al. Ceftriaxone Treatment Affects the Levels of GLT1 and ENT1 As Well As Ethanol Intake in Alcohol-Preferring Rats. J Mol Neurosci 51, 779–787 (2013). https://doi.org/10.1007/s12031-013-0064-y
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DOI: https://doi.org/10.1007/s12031-013-0064-y