α2A- But not α2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data

doi:10.1016/S0014-2999(98)00889-9

European Journal of Pharmacology

Volume 366, Issue 1, 29 January 1999, Pages 35-39

https://doi.org/10.1016/S0014-2999(98)00889-9 Get rights and content

Abstract

In this study, we used subtype-selective antagonists to determine the subtype of α₂-adrenoceptor controlling noradrenaline release in rat locus coeruleus. Noradrenaline release was measured in locus coeruleus slices using fast cyclic voltammetry at carbon fibre microelectrodes. On long stimulation trains (40 pulses, 20 Hz), the α_2A-adrenoceptor selective antagonist BRL 44408 (2-[2H-(1-methyl-1,3-dihydroisoindole) methyl]-4,5-dihydroimidazole) at 100 nM and 1 μM significantly increased stimulated noradrenaline release, whereas the α_2B/C-selective antagonist ARC 239 (2-[2[4-(o-methoxyphenyl)piperazin-1-yl] ethyl]-4,4dimethyl-1,3-(2H,4H)-isoquinolinedione) at 50 and 500 nM had no effect. On short stimuli (20 pulses, 200 Hz), the non-specific α₂-adrenoceptor agonist dexmedetomidine (10 nM) significantly decreased noradrenaline release, an effect reversed by BRL 44408 (1μM) but not by ARC 239 (500 nM). These data demonstrate that autoreceptor control of noradrenaline release in the locus coeruleus is mediated by α_2A but not α_2B/C-adrenoceptors.

Introduction

Noradrenergic cells in the locus coeruleus fire in a slow repetitive pacemaker-like fashion and their activity is determined by α₂ autoreceptors (Saunier et al., 1993). Previous studies in our laboratory have shown that these cells release noradrenaline in the rat locus coeruleus which may be detected by voltammetry (Palij and Stamford, 1994). Moreover, this noradrenaline release is under α₂-adrenoceptor control (Jorm and Stamford, 1993).

Based on molecular and pharmacological evidence, the existence of at least three different α₂-adrenoceptor subtypes (α_2A, α_2B and α_2C) is now widely accepted (Bylund et al., 1994). Each subtype has been reported to exist in the brain and messenger RNA for all three different α₂-adrenoceptor subtypes has been reported in the locus coeruleus (Tavares et al., 1996; Winzer-Serhan et al., 1997).

However, the lack of highly selective ligands to discriminate between the different α₂-adrenoceptor subtypes has made it difficult to ascribe a role for each subtype in the central functions of the α₂-adrenoceptors. More recently, a number of drugs have been demonstrated to possess subtype selectivity for α₂-adrenoceptors. The aim of the present study was therefore to determine, using these new ligands, the subtype of α₂-adrenoceptor involved in the control of noradrenaline release in the rat locus coeruleus.

Section snippets

Brain slice preparation.

Male Wistar rats (150–200 g) were stunned and then killed by rapid cervical dislocation. The brain was rapidly excised while being irrigated with ice cold artificial cerebrospinal fluid (ACSF). A vibrotome was used to obtain 350 μm thick slices containing the locus coeruleus that were transferred to the incubation chamber. The locus coeruleus slice was placed on a stainless steel grid and immobilised with a nylon meshed frame. The internal temperature of the chamber was maintained at 32°C and

Results

Electrical stimulation in the locus coeruleus evoked release of noradrenaline that was detected at a carbon fibre microelectrode adjacent to the stimulating electrode.

On long stimulus trains (40 pulses at 20 Hz) the selective α_2A-adrenoceptor antagonist BRL 44408 significantly increased stimulated noradrenaline release compared with matched controls (Fig. 1A). The effect of BRL 44408 was higher at 1 μM (+60±3%, P<0.001, n=5) than at 100 nM (+21±8%, P<0.01, n=4). In the case of the higher

Discussion

It has been demonstrated that noradrenergic cell firing appears to be under α_2A-autoreceptor control (Nörenberg et al., 1997) although recent work in dissociated rat locus coeruleus neurones has suggested that α_2B or α_2C-adrenoceptors may also modulate noradrenergic cell activity (Arima et al., 1998). Furthermore, one should be cautious of assuming that the same receptors control noradrenaline release. For instance, serotonergic cell firing in the dorsal raphe nucleus is under 5-HT_1A receptor

Acknowledgements

L.F.C. holds a postdoctoral fellowship from the Basque Government.

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Short communicationα2A- But not α2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data

Abstract

Introduction

Section snippets

Brain slice preparation.

Results

Discussion

Acknowledgements

Brain Res.

Eur. J. Pharmacol.

Neuroscience

Br. J. Anaesth.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Brain Res.

α2-Adrenoceptor-mediated potassium currents in acutely dissociated rat locus coeruleus neurones

J. Physiol. (Lond.)

Fourth International Union of Pharmacology nomenclature of adrenoceptors

Pharmacol. Rev.

Afferent projections to the locus coeruleus as determined by a retrograde tracing technique

J. Comp. Neurol.

Evidence that 5-hydroxytryptamine release in rat dorsal raphe nucleus is controlled by 5-HT1A, 5-HT1B and 5-HT1D autoreceptors

Br. J. Pharmacol.

Further studies on alpha 2-adrenoceptor subtypes involved in the modulation of [3H]noradrenaline and [3H]5-hydroxytryptamine release from rat brain cortex synaptosomes

J. Pharm. Pharmacol.

Ulstrastructural evidence for prominent postsynaptic localization of α2C-adrenergic receptors in catecholaminergic dendrites in the rat nucleus locus coeruleus

J. Comp. Neurol.

Short communication
α_2A- But not α_2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus: voltammetric data

α₂-Adrenoceptor-mediated potassium currents in acutely dissociated rat locus coeruleus neurones

Evidence that 5-hydroxytryptamine release in rat dorsal raphe nucleus is controlled by 5-HT_1A, 5-HT_1B and 5-HT_1D autoreceptors

Further studies on alpha 2-adrenoceptor subtypes involved in the modulation of [ $^{3} H$ ]noradrenaline and [ $^{3} H$ ]5-hydroxytryptamine release from rat brain cortex synaptosomes

Ulstrastructural evidence for prominent postsynaptic localization of α_2C-adrenergic receptors in catecholaminergic dendrites in the rat nucleus locus coeruleus