Abstract
Rationale
Effective pharmacological treatments to prevent cocaine relapse remain elusive. In male rats, ceftriaxone attenuates the reinstatement of cocaine-seeking while increasing glutamate transporter-1 (GLT-1) and xCT expression in the nucleus accumbens core (NAc). Despite reported sex differences in cocaine relapse, these effects have not yet been confirmed in female rats.
Objective
We investigated the effects of ceftriaxone on cue-primed reinstatement and cocaine-induced alterations in glutamatergic proteins in the NAc of female rats. Potential interactions between estrous phase and treatment were also assessed.
Method
Male and female rats self-administered cocaine in the presence of discrete cues for 12 days, followed by 2–3 weeks of extinction. Ceftriaxone or vehicle was administered daily for a minimum of 6 days immediately preceding a cue-primed reinstatement test.
Results
Total cocaine intake was greater in females than in males, but reinstatement behavior was similar. Ceftriaxone attenuated reinstatement in both sexes and was accompanied by increased expression of GLT-1a and xCT in the NAc. However, ceftriaxone attenuated reinstatement only when females were tested during met-, di-, and proestrus phases and not during estrus. A significant increase in AMPA receptor subunit GluA1 surface expression was also observed during estrus, potentially influencing reinstatement.
Conclusion
These findings extend the beneficial effects of ceftriaxone on persistent cocaine-seeking from males to females, increasing its potential as a pharmacological treatment for preventing relapse. The effects of estrus on GluA1 expression and reinstatement observed here indicate that females may need additional interventions during some phases of the menstrual cycle.
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References
Back SE, Brady KT, Jackson JL, Salstrom S, Zinzow H (2005) Gender differences in stress reactivity among cocaine-dependent individuals. Psychopharmacology 180(1):169–176. https://doi.org/10.1007/s00213-004-2129-7
Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6(7):743–749. https://doi.org/10.1038/nn1069
Becker JB (2016) Sex differences in addiction. Dialogues Clin Neurosci 18(4):395–402
Bongiovanni M, See RE (2008) A comparison of the effects of different operant training experiences and dietary restriction on the reinstatement of cocaine-seeking in rats. Pharmacol Biochem Behav 89(2):227–233. https://doi.org/10.1016/j.pbb.2007.12.019
Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, Marinelli M, Wolf ME (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454(7200):118–121. https://doi.org/10.1038/nature06995
Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20(15):RC89
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105. https://doi.org/10.1016/S0301-0082(00)00067-8
Doyle SE, Ramôa C, Garber G, Newman J, Toor Z, Lynch WJ (2014) A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype. Biol Psychiatry 76(10):810–815. https://doi.org/10.1016/j.biopsych.2014.02.005
Elman I, Karlsgodt KH, Gastfriend DR (2001) Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence. Am J Drug Alcohol Abuse 27(2):193–202. https://doi.org/10.1081/ADA-100103705
Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189(1):1–16. https://doi.org/10.1007/s00213-006-0529-6
Fattore L, Altea S, Fratta W (2008) Sex differences in drug addiction: a review of animal and human studies. Women’s Health (Lond Engl) 4(1):51–65. https://doi.org/10.2217/17455057.4.1.51
Feltenstein MW, Byrd EA, Henderson AR, See RE (2009) Attenuation of cocaine-seeking by progesterone treatment in female rats. Psychoneuroendocrinology 34(3):343–352. https://doi.org/10.1016/j.psyneuen.2008.09.014
Feltenstein MW, Henderson AR, See RE (2011) Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Psychopharmacology 216(1):53–62. https://doi.org/10.1007/s00213-011-2187-6
Fischer KD, Houston ACW, Rebec GV (2013) Role of the major glutamate transporter GLT1 in nucleus accumbens core versus shell in cue-induced cocaine-seeking behavior. J Neurosci 33(22):9319–9327. https://doi.org/10.1523/JNEUROSCI.3278-12.2013
Fuchs RA, Evans KA, Mehta RH, Case JM, See RE (2005) Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology 179(3):662–672. https://doi.org/10.1007/s00213-004-2080-7
Griffin ML, Weiss RD, Mirin SM, Lange U (1989) A comparison of male and female cocaine abusers. Arch Gen Psychiatry 46(2):122–126. https://doi.org/10.1001/archpsyc.1989.01810020024005
Johnson M (2012) Loading controls for Western blots. Mater Methods 2:114. 10.13070/mm.en.2.114
Kerstetter KA, Aguilar VR, Parrish AB, Kippin TE (2008) Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats. Psychopharmacology 198(1):63–75. https://doi.org/10.1007/s00213-008-1089-8
Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, See RE (2005) Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology 182(2):245–252. https://doi.org/10.1007/s00213-005-0071-y
Knackstedt LA, Melendez RI, Kalivas PW (2010a) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67(1):81–84. https://doi.org/10.1016/j.biopsych.2009.07.018
Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW (2010b) Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci 30(23):7984–7992. https://doi.org/10.1523/JNEUROSCI.1244-10.2010
LaCrosse AL, Hill K, Knackstedt LA (2016) Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression. Eur Neuropsychopharmacol 26(2):186–194. https://doi.org/10.1016/j.euroneuro.2015.12.022
Lacrosse AL, O’Donovan SM, Sepulveda-Orengo MT et al (2017) Contrasting the role of xCT and GLT-1 upregulation in the ability of ceftriaxone to attenuate the cue-induced reinstatement of cocaine-seeking and normalize AMPA receptor subunit expression. J Neurosci 37(24):5809–5821. https://doi.org/10.1523/JNEUROSCI.3717-16.2017
Lebron-Milad K, Milad MR (2012) Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders. Biol Mood Anxiety Disord 2(1):3. https://doi.org/10.1186/2045-5380-2-3
Liu SJ, Zukin RS (2007) Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci 30(3):126–134. https://doi.org/10.1016/j.tins.2007.01.006
Marcondes FK, Bianchi FJ, Tanno AP (2002) Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 62(4a):609–614. https://doi.org/10.1590/S1519-69842002000400008
Martinez LA, Gross KS, Himmler BT, Emmitt NL, Peterson BM, Zlebnik NE, Foster Olive M, Carroll ME, Meisel RL, Mermelstein PG (2016) Estradiol facilitation of cocaine self-administration in female rats requires activation of mGluR5. Eneuro 3(5). https://doi.org/10.1523/ENEURO.0140-16.2016
McCance-Katz EF, Carroll KM, Rounsaville BJ (1999) Gender differences in treatment-seeking cocaine abusers--implications for treatment and prognosis. Am J Addict 8(4):300–311
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23(8):3531–3537
McLean AC, Valenzuela N, Fai S, Bennett SAL (2012) Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp e4389. https://doi.org/10.3791/4389
Peterson BM, Mermelstein PG, Meisel RL (2015) Estradiol mediates dendritic spine plasticity in the nucleus accumbens core through activation of mGluR5. Brain Struct Funct 220(4):2415–2422. https://doi.org/10.1007/s00429-014-0794-9
Potter DA, Moreno A, Luther MF et al (1998) Effects of follicular-phase cocaine administration on menstrual and ovarian cyclicity in rhesus monkeys. Am J Obstet Gynecol 178(1):118–125. https://doi.org/10.1016/S0002-9378(98)70637-4
Potter DA, Luther MF, Eddy CA et al (1999) Low-dose follicular-phase cocaine administration disrupts menstrual and ovarian cyclicity in rhesus monkeys. J Soc Gynecol Investig 6(2):88–94. https://doi.org/10.1177/107155769900600207
Rimmele TS, Rosenberg PA (2016) GLT-1: the elusive presynaptic glutamate transporter. Neurochem Int 98:19–28. https://doi.org/10.1016/j.neuint.2016.04.010
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 Z, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433(7021):73–77. https://doi.org/10.1038/nature03180
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(29):9239–9243. https://doi.org/10.1523/JNEUROSCI.1746-09.2009
Schmittner J, Schroeder JR, Epstein DH, Preston KL (2005) Menstrual cycle length during methadone maintenance. Addiction 100(6):829–836. https://doi.org/10.1111/j.1360-0443.2005.01091.x
Smith ACW, Scofield MD, Heinsbroek JA, Gipson CD, Neuhofer D, Roberts-Wolfe DJ, Spencer S, Garcia-Keller C, Stankeviciute NM, Smith RJ, Allen NP, Lorang MR, Griffin WC III, Boger HA, Kalivas PW (2017) Accumbens nNOS interneurons regulate cocaine relapse. J Neurosci 37(4):742–756. https://doi.org/10.1523/JNEUROSCI.2673-16.2017
Sondheimer I, Knackstedt LA (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(1):252–258. https://doi.org/10.1016/j.bbr.2011.07.041
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. https://doi.org/10.1523/JNEUROSCI.1976-12.2012
Trivedi RR, Bhattacharyya S (2012) Constitutive internalization and recycling of metabotropic glutamate receptor 5 (mGluR5). Biochem Biophys Res Commun 427(1):185–190. https://doi.org/10.1016/j.bbrc.2012.09.040
Wang X, Moussawi K, Knackstedt L, Shen H, Kalivas PW (2013) Role of mGluR5 neurotransmission in reinstated cocaine-seeking. Addict Biol 18(1):40–49. https://doi.org/10.1111/j.1369-1600.2011.00432.x
Ward SJ, Rasmussen BA, Corley G, Henry C, Kim JK, Walker EA, Rawls SM (2011) Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice. Behav Pharmacol 22(4):370–373. https://doi.org/10.1097/FBP.0b013e3283473c10
Weiland A, Garcia S, Knackstedt LA (2015) Ceftriaxone and cefazolin attenuate the cue-primed reinstatement of alcohol-seeking. Front Pharmacol 6:44. https://doi.org/10.3389/fphar.2015.00044
White SL, Vassoler FM, Schmidt HD, Pierce RC, Wimmer ME (2016) Enhanced anxiety in the male offspring of sires that self-administered cocaine. Addict Biol 21(4):802–810. https://doi.org/10.1111/adb.12258
Xie X, Lasseter HC, Ramirez DR, Ponds KCL, Wells AM, Fuchs RA (2012) Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats. Addict Biol 17(2):287–299. https://doi.org/10.1111/j.1369-1600.2011.00325.x
Acknowledgements
The authors would like to thank Lizhen Wu for her excellent technical assistance on this project.
Funding
This work was funded by National Institutes of Health grants DA033436 and DA037270 awarded to L.A.K.
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All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Florida and performed in accordance with the Guide for the Care and Use of Laboratory Animals.
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Bechard, A.R., Hamor, P.U., Schwendt, M. et al. The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: estrous cycle effects on behavior and protein expression in the nucleus accumbens. Psychopharmacology 235, 837–848 (2018). https://doi.org/10.1007/s00213-017-4802-7
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DOI: https://doi.org/10.1007/s00213-017-4802-7