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Effect of ceftriaxone and topiramate treatments on naltrexone-precipitated morphine withdrawal and glutamate receptor desensitization in the rat locus coeruleus

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Abstract

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.

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Abbreviations

ANOVA:

Analysis of variance

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

aCSF:

Artificial cerebrospinal fluid

CFT:

Ceftriaxone

DHK:

Dihydrokainic acid

EC50 :

Half maximal effective concentration

E max :

Maximal effect

EAAT:

Excitatory amino acid transporter

EAAT2:

Type-2 excitatory amino acid transporter

GABA:

Gamma-aminobutyric acid

iGluR:

Ionotropic glutamate receptor

KCl:

Potassium chloride

LC:

Locus coeruleus

mGluR:

Metabotropic glutamate receptor

MOR:

μ opioid receptor

Nav channel:

Voltage-dependent sodium channel

NMDA:

N-methyl-d-aspartic acid

S.E.M.:

Standard error of the mean

TPM:

Topiramate

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Acknowledgments

This work was supported by the Ministerio de Ciencia e Innovación [Grant SAF2008-03612] and the University of the Basque Country (UPV/EHU) [Grant GIU11/27 and Grant GIU14/29]. Pineda’s research group takes part in a network unit supported by the University of the Basque Country [UFI 11/35]. MC Medrano was supported by a predoctoral fellowship from the Basque Government. The experiments comply with the current laws of Spain.

Conflict of interest

There are no conflict of interest and no financial relationship with the Organization that sponsored the research.

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  1. Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country (UPV/EHU), B° Sarriena s/n, 48940, Leioa, Bizkaia, Spain

    María Carmen Medrano, Aitziber Mendiguren & Joseba Pineda

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  1. María Carmen Medrano
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  2. Aitziber Mendiguren
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  3. Joseba Pineda
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Correspondence to Joseba Pineda.

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Medrano, M.C., Mendiguren, A. & Pineda, J. Effect of ceftriaxone and topiramate treatments on naltrexone-precipitated morphine withdrawal and glutamate receptor desensitization in the rat locus coeruleus. Psychopharmacology 232, 2795–2809 (2015). https://doi.org/10.1007/s00213-015-3913-2

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