Functional and morphological characterization of glutamate transporters in the rat locus coeruleus
Br J Pharmacol. 2013-07-26; 169(8): 1781-1794
DOI: 10.1111/bph.12235
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Medrano MC(1), Gerrikagoitia I, Martínez-Millán L, Mendiguren A, Pineda J.
Author information:
(1)Department of Pharmacology, Faculty of Medicine and Odontology, University of
the Basque Country (UPV/ EHU), Bizkaia, Spain.
BACKGROUND AND PURPOSE: Excitatory amino acid transporters (EAATs) in the CNS
contribute to the clearance of glutamate released during neurotransmission. The
aim of this study was to explore the role of EAATs in the regulation of locus
coeruleus (LC) neurons by glutamate.
EXPERIMENTAL APPROACH: We measured the effect of different EAAT subtype
inhibitors/enhancers on glutamate- and KCl-induced activation of LC neurons in
rat slices. EAAT2-3 expression in the LC was also characterized by
immunohistochemistry.
KEY RESULTS: The EAAT2-5 inhibitor DL-threo-β-benzyloxaspartic acid (100 μM), but
not the EAAT2, 4, 5 inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (100 μM)
or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 μM), enhanced the glutamate-
and KCl-induced activation of the firing rate of LC neurons. These effects were
blocked by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK
(100 μM) was the only EAAT inhibitor that increased the spontaneous firing rate
of LC cells, an effect that was due to inhibition of EAAT2 and subsequent AMPA
receptor activation. Chronic treatment with ceftriaxone (200 mg·kg(-1) i.p., once
daily, 7 days), an EAAT2 expression enhancer, increased the actions of glutamate
and DHK, suggesting a functional impact of EAAT2 up-regulation on the
glutamatergic system. Immuhistochemical data revealed the presence of EAAT2 and
EAAT3 surrounding noradrenergic neurons and EAAT2 on glial cells in the LC.
CONCLUSIONS AND IMPLICATIONS: These results remark the importance of EAAT2 and
EAAT3 in the regulation of rat LC by glutamate. Neuronal EAAT3 would be
responsible for terminating the action of synaptically released glutamate,
whereas glial EAAT2 would regulate tonic glutamate concentrations in this
nucleus.
© 2013 The British Pharmacological Society.