Agmatine does not have activity at α2-adrenoceptors which modulate the firing rate of locus coeruleus neurones: an electrophysiological study in rat
ABSTRACT Agmatine (decarboxylated arginine) has been proposed as an endogenous ligand for non-adrenoceptor, imidazoline binding sites, but also binds to α2-adrenoceptors. The interaction of agmatine with α2-adrenoceptors was evaluated by studying the effect of agmatine on the firing rate of locus coeruleus (LC) neurones using extracellular recordings in anesthetized rats and rat brain slices. In vivo, local application of agmatine into the LC caused a slight and short-lasting increase in cell firing rate (P < 0.005). In vitro, agmatine failed to change the firing rate of LC neurones nor did it antagonize the inhibitory effect of noradrenaline on these cells. Since α2-adrenoceptors are known to inhibit the firing of LC cells, we conclude that agmatine does not have agonist or antagonist properties at α2-adrenoceptors of these neurones.
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ABSTRACT: Locus coeruleus (LC) neurons respond to sensory stimuli with a glutamate-triggered burst of spikes followed by an inhibition. The aim of our work was to characterize the inhibitory effect of glutamate in the LC. Single-unit extracellular and patch-clamp recordings were performed to examine glutamate responses in rat brain slices containing the LC. Glutamate caused an initial activation followed by a late post-activation inhibition (PAI). Both effects were blocked by an AMPA/kainate receptor antagonist but not by NMDA or metabotropic glutamate receptor antagonists. All glutamate receptor agonists were able to activate neurons, but only AMPA and quisqualate caused inhibition. In neurons clamped at -60 mV, glutamate and AMPA induced inward, followed by outward, currents, with the latter reversing polarity at -110 mV. Glutamate-induced PAI was not modified by alpha(2)-adrenoceptor, micro opioid, A(1) adenosine and GABA(A/B) receptor antagonists or Ca(2+)-dependent release blockade, but it was reduced by raising the extracellular K(+) concentration. Glutamate-induced PAI was not affected by several potassium channel, Na(+)/K(+) pump, PKC and neuronal NO synthase inhibitors or lowering the extracellular Ca(2+) concentration. The Na(+)-activated K channel opener bithionol concentration-dependently potentiated glutamate-induced PAI, whereas partial (80%) Na(+) replacement reduced glutamate- and AMPA-induced PAI. Finally, reverse transcription polymerase chain reaction assays showed the presence of mRNA for the Ca(2+)-impermeable GluR2 subunit in the LC. Glutamate induces a late PAI in the LC, which may be mediated by a novel postsynaptic Na(+)-dependent K(+) current triggered by AMPA/kainate receptors.British Journal of Pharmacology 03/2009; 156(4):649-61. · 5.07 Impact Factor
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ABSTRACT: Agmatine [2-(4-aminobutyl)guanidine] is an endogenous amine proposed as a neurotransmitter/neuromodulator that binds to multiple target receptors in brain. Besides, many central and peripheral functions, agmatine have been implicated in the process of drug addiction. The purpose of the present study was to examine the effects of centrally injected agmatine on nicotine induced locomotor sensitization in Swiss male mice. Our data shows that repeated injections of nicotine (0.4 mg/kg, sc, twice daily for 7 days) gradually increased locomotion during 7 days development period or after 3 days (nicotine) withdrawal phase challenged with nicotine (0.4 mg/kg, sc) on day 11. Mice were pretreated with agmatine (40-80 microg, icv) or agents known to increase endogenous brain agmatine levels [e.g. an agmatine biosynthetic precursor, L-arginine (80 microg, icv), ornithine decarboxylase inhibitor, difluoromethyl-ornithine (50 microg, icv), diamine oxidase inhibitor, aminoguanidine (25 microg, icv) and agmatinase inhibitor, arcaine (50 microg, icv)] 30 min before daily first nicotine injection or during nicotine withdrawal phase. All these treatments attenuated the development as well as incubation of locomotor sensitization to nicotine. Coadministration of agmatine (20 microg, icv) and alpha(2)-adrenoreceptors agonist, clonidine (0.1 microg, icv) evoked synergistic inhibition of nicotine sensitization. Conversely, prior administration of alpha(2)-adrenoceptor antagonist, yohimbine (5mg/kg, ip) or idazoxan (0.4 mg/kg, ip) reversed the inhibitory effect of agmatine on nicotine sensitization. There was no significant difference in activity between mice injected with any of these agents/saline alone and saline/saline groups. These data indicate that agmatine attenuates nicotine induced locomotor sensitization via a mechanism which may involve alpha(2)-adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of nicotine addiction and deserve further investigations.Behavioural brain research 05/2010; 213(2):161-74. · 3.22 Impact Factor
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ABSTRACT: Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met(5)-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.Frontiers in Behavioral Neuroscience 01/2010; 3:60. · 4.76 Impact Factor