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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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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DOI: https://doi.org/10.1007/s00213-015-3913-2