Effect of ceftriaxone and topiramate treatments on naltrexone-precipitated morphine withdrawal and glutamate receptor desensitization in the rat locus coeruleus
Psychopharmacology. 2015-03-20; 232(15): 2795-2809
DOI: 10.1007/s00213-015-3913-2
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Medrano MC(1), Mendiguren A, Pineda J.
Author information:
(1)Department of Pharmacology, Faculty of Medicine and Odontology, University of
the Basque Country (UPV/EHU), B° Sarriena s/n, 48940, Leioa, Bizkaia, Spain.
RATIONALE: 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.
OBJECTIVES: 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.