Modulation of neurotransmission in locus coeruleus by metabotropic glutamate receptors.

Title: Modulation of neurotransmission in locus coeruleus by metabotropic glutamate receptors.
Authors: Dubé, Gilles R.
Date: 1998
Abstract: The locus coeruleus, a small group of pontine neurons, is the most prominent noradrenaline-containing nucleus in the central nervous system. Activity of this nucleus is thought to modulate the function throughout the brain through its widespread afferent network. Here, the effects of selective activation of metabotropic glutamate receptors on synaptic transmission in intracellularly recorded locus coeruleus neurons in brain slice preparations are described. Perfusion of either t-ACPD (0.1-500 $\mu$M) or L-AP4 (0.1-500 $\mu$M) caused a depression of excitatory postsynaptic potentials in a dope-dependent fashion to about 70% inhibition. Both agonists exerted their effects with estimated EC$\sb{50}$s of 2.6 $\mu$M and 11.5 $\mu$M for L-AP4 and t-ACPD respectively. Both t-ACPD and L-AP4 produced an increase in paired-pulse facilitation, and failed to change the response of locus coeruleus neurons to focally-applied glutamate, indicating a presynaptic locus of action. Both group II and III metabotropic glutamate receptors have been shown to be coupled to a G$\rm\sb{i/o}$-protein and, in certain systems, activation of these receptors results in a decrease of forskolin-stimulated cAMP levels. However, many all G$\rm\sb{i/o}$-coupled receptors have also been shown to block calcium channels in different cell types. Thus, several tests were carried out in an attempt to define the signal transduction pathway involved in the t-ACPD and L-AP4 effects in locus coeruleus. In a first set of experiments, N-ethylmaleimide, a compound known to disrupt the interaction between G$\rm\sb{i/o}$ proteins and calcium channels, was tested. Pretreatment of slices with N-ethylmaleimide (50-100 $\mu$M, 15 min.) resulted in an almost complete block of the effects of t-ACPD and L-AP4. In a second set of experiments, perfusion of a "cAMP cocktail" (200$\mu$M 8-bromo-cAMP, 20$\mu$M forskolin and 1mM IBMX) was tested on the response of locus coeruleus to t-ACPD and LAP4. In the last part of this study, the functional role of synaptically-released excitatory amino acid on metabotropic glutamate receptors in locus coeruleus was investigated. When single stimuli were applied to the afferents at intervals greater than 200ms, the amplitude of the second (test (T)) excitatory postsynaptic potential was identical in amplitude to the first (control(C)). However, when a train of stimulation was delivered prior to T, the amplitude of T was consistently smaller than C. The depression was dependent on the frequency and duration of the train and the interval between the train and T. In most experiments, optimal inhibition was observed with a 300ms, 70 Hz train delivered 600ms prior to the test EPSP. This activity-dependent depression of excitatory postsynaptic potentials was enhanced in the presence of an excitatory amino acid uptake inhibitor L-trans-pyrrolidine-2, 4-dicarboxylic acid (t-PDC, 100 $\mu$M) from a T/C ratio of 0.80 $\pm$ 0.03 (mean $\pm$ SEM) in control to 0.68 $\pm$ 0.05 in t-PDC. Together, the studies described above provide evidence that activation of either of two different presynaptic metabotropic glutamate receptors belonging to group II and m, respectively, produce a decrease in excitatory synaptic transmission in locus coeruleus through an undetermined mechanism but in a cAMP-independent manner. (Abstract shortened by UMI.)
CollectionThèses, 1910 - 2010 // Theses, 1910 - 2010
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