Research reportFunctional and pharmacological characterization of the modulatory role of serotonin on the firing activity of locus coeruleus norepinephrine neurons
Introduction
It is well established that norepinephrine (NE) neurons modulate the serotonin (5-HT) system. In the brainstem, dorsal raphe (DR) 5-HT neurons receive ascending NE neuron afferents originating from the locus coeruleus (LC), a nucleus almost exclusively responsible for the NE innervation of the forebrain [4], [1], [37], [47]. Interactions between LC and DR impart a significant NE influence on the 5-HT system [47], [32] and evidence has recently accumulated for the inverse relationship between these two nuclei as well, for review see Refs. [31] and [48]. For instance, Kaehler et al. [35] reported that descending projections from the DR to the LC account for at least 50% of the 5-HT innervation of this nucleus. These reciprocal monoaminergic interactions have been linked to the efficacy of antidepressant drugs in anxiety and affective disorders, in which treatment, but not necessarily etiology, of these disorders relies on altered NE and 5-HT transmission [15]. Interestingly, not all antidepressant drugs induce these neurochemical changes via the same mechanisms and agents that selectively target only one of these systems almost invariably produce alterations in both monoaminergic systems after chronic administration [9].
The selective serotonin reuptake inhibitors (SSRIs) are now considered as a first line therapeutic approach in the treatment of affective and many anxiety disorders. However, as with all antidepressants, they require an administration of at least 2 weeks before a clear beneficial effect can manifest itself. Long-term, but not acute or short-term SSRI administration increases the net output of 5-HT neurons, via the desensitization of 5-HT1A and 5-HT1B autoreceptors in the presence of 5-HT reuptake blockade, and induces an attenuation in the spontaneous firing activity of LC NE neurons [6], [54], [55] with a time-course that correlates with their anxiolytic and antidepressant responses (see [53] for review).
Various 5-HT receptor subtypes, especially the 5-HT1A and 5-HT2A receptors, are believed to be implicated in the antidepressant and anti-panic effects of long-term SSRI treatment. Activation of these two receptor subtypes, which are present in the LC [39], [57], alters NE neuron firing, however, in opposite directions. On the one hand, the enhancement of the firing rate of LC neurons produced by the intravenous administration of the 5-HT1A receptor agonist 8-OH-DPAT is abolished in rats treated with antidepressants which selectively inhibit either 5-HT or NE transporter reuptake [50], [51], [55]. On the other hand, the attenuation of the firing rate of LC neurons induced by the 5-HT2 receptor agonist DOI is decreased in long-term SSRI-treated rats, but unaltered by a NE reuptake blocker [55]. Thus, the therapeutic effect of drugs selective for the 5-HT system, like SSRIs, could be mediated in part by a modification of the efficacy of 5-HT transmission to the LC via the desensitization of 5-HT1A and 5-HT2 receptors, but this possibility needed to be better documented.
In a first series of experiments, selective lesions of 5-HT neurons were performed to further delineate whether 5-HT neurons are necessary to mediate the 5-HT1A and 5-HT2A receptor effects that modulate NE neuron firing. In a second series of experiments, the effects of the selective 5-HT2A and α2-adrenoceptor antagonists MDL 100,907 and idazoxan, respectively, were assessed on the firing activity of LC NE neurons in controls and 21-day paroxetine treated rats. The latter study was performed to ascertain whether enhanced 5-HT availability and 5-HT receptor activation/alterations in the LC from prolonged SSRI administration [33], [54] may be mediating the attenuation of NE neuron activity by overactivating inhibitory 5-HT2A receptors [52]. Given the reciprocal interactions between these two monoaminergic systems, it also had to be ensured that the attenuation on NE activity from sustained SSRI administration was truly a 5-HT mediated event and not to another receptor alteration. Thus, the response to idazoxan on LC firing activity was also evaluated in control and 21-day paroxetine treated rats.
Section snippets
Animals
The experiments were carried out in male Sprague–Dawley rats (Charles River, St. Constant, Québec, Canada) weighing between 300 and 325 g were kept under standard laboratory conditions (12:12 light–dark cycle with access to food and water ad libitum). Rats were anaesthetized with chloral hydrate (400 mg/kg, i.p.) and mounted in a stereotaxic apparatus (David Kopf Instuments). Supplemental doses (100 mg kg−1, i.p.) were given to prevent any nociceptive reaction to pinching of the hind paw. Body
Effect of MDL 100,907 on WAY 100,635-mediated attenuation of NE neuron firing activity
Systemic injection of the selective 5-HT1A receptor antagonist WAY 100,635 decreases the firing rate of NE neurons which can be prevented by a previous administration of drugs with 5-HT2A antagonistic properties, but that were not selective for the latter receptor [31]. Given that MDL 100,907 is currently the only selective 5-HT2A receptor antagonist available, it was deemed mandatory to assess whether this compound could reverse, rather than prevent, the effect of WAY 100,635 on LC firing
Discussion
The results of the present study first indicate the inhibitory effects of the selective 5-HT1A receptor antagonist WAY 100,635 on LC NE neuron firing is mediated through an augmented 5-HT transmission at 5-HT2A receptors. This is based on the premise that the suppressant effect of WAY 100,635 on NE neuron firing is dependent on intact 5-HT neurons, as their destruction prevents its inhibitory action [33]. Then, acute administration of the selective 5-HT2A receptor antagonist MDL 100,907 by
Acknowledgements
This work was supported by a Medical Research Government of Canada (MRC) Grant (MT-11410 to P.B.), a MRC doctoral award (MRC-1554 to STS), a Fonds pour la Formation de Chercheurs et L’Aide à la recherche-Fonds de la Recherche en Santé du Québec (FRSQ-FCAR-Santé-68803 to STS), and by salary support from the University of Florida to PB and STS.
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