title: Effect of ceftriaxone and topiramate treatments on naltrexone-precipitated morphine withdrawal and glutamate receptor desensitization in the rat locus coeruleus.
abstract: BACKGROUND
  Morphine withdrawal is associated with a hyperactivity of locus coeruleus (LC) neurons by an elevated glutamate neurotransmission in this nucleus. We postulate that reductions in the amount of glutamate in the LC by enhancing its reuptake or inhibiting its release could attenuate the behavioral and cellular consequences of morphine withdrawal.
  
  
  OBJECTIVE
  We investigated the effect of chronic treatment with ceftriaxone (CFT), an excitatory amino acid transporter (EAAT2) enhancer, and acute administration of topiramate (TPM), a glutamate release inhibitor, on morphine withdrawal syndrome and withdrawal-induced glutamate receptor (GluR) desensitization in LC neurons from morphine-dependent rats.
  
  
  METHODS
  Morphine withdrawal behavior was measured after naltrexone administration in rats implanted with a morphine (200 mg kg(-1)) emulsion for 3 days. GluR desensitization in the LC was assessed by performing concentration-effect curves for glutamate by extracellular electrophysiological recordings in vitro.
  
  
  RESULTS
  Treatments with CFT or TPM reduced, in a dose-related manner, the total behavioral score of naltrexone-precipitated morphine withdrawal. CFT and TPM, at doses that were effective in behavioral tests, also reduced the induction of GluR desensitization normally occurring in LC neurons from morphine-dependent rats. Acute treatment with the specific EAAT2 inhibitor dihydrokainic acid (DHK) prevented the effect of CFT on withdrawal syndrome and GluR desensitization. Perfusion with TPM inhibited KCl-evoked but not glutamate-induced activation of LC neurons in vitro.
  
  
  CONCLUSIONS
  Our results suggest that a reduction of synaptic concentrations of glutamate by enhancing EAAT2-mediated uptake or inhibiting glutamate release alleviates the behavioral response and the cellular changes in the LC during opiate withdrawal.
authors: Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/EHU), B° Sarriena s/n, 48940, Leioa, Bizkaia, Spain.
authors: María Carmen
authors: MC
authors: Medrano
authors: Aitziber
authors: A
authors: Mendiguren
authors: Joseba
authors: J
authors: Pineda
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009021:Morphine Dependence / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism; D000077236:Topiramate
chemical_list: D000701:Analgesics, Opioid; D017470:Receptors, Glutamate; D000077236:Topiramate; D005632:Fructose; D018698:Glutamic Acid; D002443:Ceftriaxone