Abstract
Rationale
Several studies suggest that repeated nicotine administration causes alterations in glutaminergic transmission that may play an important role in developing and maintaining nicotine addiction. Chronic nicotine administration in rats decreases the expression of the glutamate transporter-1 (GLT-1) and cysteine–glutamate exchanger (system xC−) in the nucleus accumbens. We hypothesized that ceftriaxone, a GLT-1 and system xC− activator, would decrease murine behavioral aspects of nicotine dependence.
Objective
This study aimed to investigate the effect of repeated ceftriaxone administration on the behavioral effects of nicotine using mouse models of conditioned reward and withdrawal.
Method
Using male ICR mice, the ability of repeated ceftriaxone injections to modulate the development and reinstatement of a nicotine-conditioned place preference (CPP) was evaluated. Additionally, nicotine withdrawal-associated signs were assessed. These included both physical (somatic signs and hyperalgesia) and affective (anxiety-related behaviors) withdrawal signs in mice. Finally, the effects of ceftriaxone on nicotine-induced antinociception and hypothermia after acute nicotine injection were measured.
Result
Ceftriaxone had no effect on the development of nicotine preference but significantly attenuated nicotine-induced reinstatement of CPP. Furthermore, ceftriaxone reversed all nicotine withdrawal signs measured in mice.
Conclusion
Altogether, these findings show that a β-lactam antibiotic reduces nicotine withdrawal and nicotine-seeking behavior. Our results suggest that the documented efficacy of ceftriaxone against cocaine and morphine dependence-related behaviors effects extends to nicotine.
Similar content being viewed by others
Abbreviations
- CPP:
-
Conditioned place preference
- s.c.:
-
Subcutaneous injection
- i.p.:
-
Intraperitoneal injection
- GLT-1:
-
Glial glutamate transporter-1
- System xC :
-
Cysteine-glutamate exchanger
References
Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. GLIA 32:1–14. doi:10.1002/1098-1136(200010)32:1<1:AID-GLIA10>3.0.CO2-W
Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW (2002) The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 22:9134–41
Castane A, Berrendero F, Maldonado R (2005) The role of the cannabinoid system in nicotine addiction. Pharmaco Biochem Behav 81:381–386. doi:10.1016/j.pbb.2005.01.025
Damaj MI, Glassco W, Aceto MD, Martin BR (1999) Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist. J Pharmacol Exp Ther 291:390–398
D’Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79
De Bundel D, Schallier A, Loyens E, Fernando R, Miyashita H, Van Liefferinge J, Vermoesen K, Bannai S, Sato H, Michotte Y, Smolders I, Massie A (2011) Loss of system x(c)− does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J Neurosci 31(15):5792–5803
Jackson KJ, Martin BR, Changeux JP, Damaj MI (2008) Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J Pharmacol Exp Ther 325:302–312
Jackson KJ, McLaughlin JP, Carroll FI, Damaj MI (2012) Effects of the kappa opioid receptor antagonist, norbinaltorphimine, on stress and drug-induced reinstatement of nicotine-conditioned place preference in mice. Psychopharmacology (Berl). doi:10.1007/s00213-012-2716-y
Kau KS, Madayag A, Mantsch JR, Grier MD, Abdulhameed O, Baker DA (2008) Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking. Neuroscience 155:530–537. doi:10.1016/j.neuroscience.2008.06.010
Kenny P, Markou A (2004) The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol Sci 25:265–272. doi:10.1016/j.tips.2004.03.009
Knackstedt L, LaRowe S, Mardikian P, Malcolm R, Upadhyaya H, Hedden S, Markou A, Kalivas P (2009) The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry 65:841–845
Knackstedt L, Melendez R, Kalivas P (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67:81–84. doi:10.1016/j.biopsych.2009.07.018
Kota D, Martin BR, Robinson SE, Damaj MI (2007) Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther 322:399–407. doi:10.1124/jpet.107.121616
Lewerenz J, Albrecht P, Tien ML, Henke N, Karumbayaram S, Kornblum HI et al (2009) Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. J Neurochem 111(2):332–343
Liechti M, Lhuillier L, Kaupmann K, Markou A (2007) Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. J Neurosci 27:9077–9085. doi:10.1523/JNEUROSCI.1766-07.2007
Liechti M, Markou A (2007) Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats. Eur J Pharmacol 554:164–174. doi:10.1016/j.ejphar.2006.10.011
Liechti M, Markou A (2008) Role of the glutamatergic system in nicotine dependence: implications for the discovery and development of new pharmacological smoking cessation therapies. CNS Drugs 22:705–724
Mansvelder H, Keath JR, McGehee D (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33:905–919
Markou A (2008) Review. Neurobiology of nicotine dependence. Phil Trans R Soc Biol Sci 363:3159–3168. doi:10.1098/rstb.2008.0095
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. doi:10.1016/j.neuroscience.2008.02.004
Rawls SM, Tallarida R, Robinson W, Amin M (2007) The beta-lactam antibiotic, ceftriaxone, attenuates morphine-evoked hyperthermia in rats. Br J Pharmacol 151:1095–1102. doi:10.1038/sj.bjp.0707309
Rawls S, Zielinski M, Patel H, Sacavage S, Baron D, Patel D (2010) Beta-lactam antibiotic reduces morphine analgesic tolerance in rats through GLT-1 transporter activation. Drug Alcohol Depend 107:261–263. doi:10.1016/j.drugalcdep.2009.10.010
Reid MS, Fox L, Ho LB, Berger SP (2000) Nicotine stimulation of extracellular glutamate levels in the nucleus accumbens: neuropharmacological characterization. Synapse 35:129–136, 2-D
Rothstein JD, Martin L, Levey AI, Dykes Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994) Localization of neuronal and glial glutamate transporters. Neuron 13:713–725
Rothstein J, Patel S, Regan M, Haenggeli C, Huang Y, Bergles D, Jin L, Dykes Hoberg M, Vidensky S, Chung D, Toan S, Bruijn L, Su Z, Gupta P, Fisher P (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77. doi:10.1038/nature03180
Saellstroem Baum S, Huebner A, Krimphove M, Morgenstern R, Badawy AA, Spies C (2006) Nicotine stimulation on extracellular glutamate levels in the nucleus accumbens of ethanol-withdrawn rats in vivo. Alcohol Clin Exp Res 30:1414–1421. doi:10.1111/j.1530-0277.2006.00169.x
Sari Y, Smith K, Ali P, Rebec G (2009) Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J Neurosci 29:9239–9243. doi:10.1523/JNEUROSCI.1746-09.2009
Schroeder J, Quick K, Landry P, Rawls S (2011) Glutamate transporter activation enhances nicotine antinociception and attenuates nicotine analgesic tolerance. NeuroReport 22:970–973. doi:10.1097/WNR.0b013e32834d87eb
Sondheimer I, Knackstedt L (2011) Ceftriaxone prevents the induction of cocaine sensitization and produces enduring attenuation of cue- and cocaine-primed reinstatement of cocaine-seeking. Behav Brain Res 225:252–258. doi:10.1016/j.bbr.2011.07.041
Stoker A, Olivier B, Markou A (2012) Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal. Psychopharmacology (Berl) 221:317–327. doi:10.1007/s00213-011-2578-8
Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacol (Berl) 117:2–10
Trantham-Davidson H, Lalumiere RT, Reissner KJ, Kalivas PW, Knackstedt LA (2012) Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. J Neurosci 32(36):12406–12410
Walters C, Brown S, Changeux J, Martin B, Damaj MI (2006) The beta2 but not alpha7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice. Psychopharmacol (Berl) 184:339–344. doi:10.1007/s00213-005-0295-x
Watkins SS, Koob GF, Markou A (2000) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nico Tob Res 2:19–37
Acknowledgments
This work was supported by the National Institute of Drug Abuse grant DA-12610 to MID. The authors wish to thank Cindy Evans and Tie Han for their technical assistance with this study. There are no conflicts of interest to disclose for this research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Alajaji, M., Bowers, M.S., Knackstedt, L. et al. Effects of the beta-lactam antibiotic ceftriaxone on nicotine withdrawal and nicotine-induced reinstatement of preference in mice. Psychopharmacology 228, 419–426 (2013). https://doi.org/10.1007/s00213-013-3047-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-013-3047-3