Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: Comparison with antidepressant drugs
Introduction
Since Kramer et al. [45] first reported in 1998 that the substance P (SP) antagonist MK-869 had antidepressant properties in humans, considerable research has been done on the mechanism of action of neurokinin (NK) 1 antagonists. The studies have been focused on interactions between neurokinin-1 (NK1) receptors and serotonin (5-HT) and norepinephrine (NE), which are the main monoamines implicated in the mechanism of action of antidepressants, and on the effects of NK1 antagonists in the hippocampus, one of the major brain structures in which antidepressants exert profound actions.
The main goal of this review is to summarize the effects of antidepressants on 5-HT and NE neurotransmission and on hippocampus pyramidal neurons, and to compare these effects to those of NK1 antagonists.
Whether antidepressants exert their action by correcting a monoamine deficiency, or by upregulating or augmenting the function of intact monoamine systems is still a matter of debate [25], [59]. Several classes of drugs acting on monoaminergic systems exert a clear antidepressant effect through various mechanisms (Fig. 1). Extensive electrophysiological investigations carried out in our laboratory have documented that several types of antidepressant treatments enhance 5-HT neurotransmission in the rat hippocampus [10]. This net effect, that is common to the major types of antidepressant treatments is, however, mediated via different mechanisms (Table 1). Electroconvulsive shock therapy (ECT) probably increases the release of many neurotransmitters, but in particular it enhances the responsiveness of 5-HT1A receptors in hippocampus [18], as do tricyclics (TCAs) [13]. Since some TCAs block the reuptake of 5-HT and/or NE, but some like trimipramine and iprindole do not affect the reuptake of either neurotransmitters [40], the sensitization of postsynaptic 5-HT1A receptors by some TCAs could account for their therapeutic effect in depression. Selective serotonin reuptake inhibitors (SSRIs) rapidly increase 5-HT levels in the brainstem, which activates 5-HT1A autoreceptors. As these receptors exert a negative feedback on 5-HT neuronal firing, and consequently on overall neurotransmission, it is only when they are desensitized that SSRIs can exert their therapeutic actions [10]. SSRIs do not affect the sensitivity of postsynaptic 5-HT1A receptors, but attenuate the function of terminal 5-HT1B autoreceptors, thus increasing the release of 5-HT in the terminal areas [13]. Similarly, monoamine oxidase inhibitors (MAOIs), desensitize the 5-HT1A autoreceptors after a delay similar to that of SSRIs [8]. As well, they desensitize α2-adrenergic heteroreceptors on 5-HT terminals, thereby contributing to attenuate the negative feedback of NE on 5-HT release at the postsynaptic level [58]. The α2-antagonist mirtazapine and the NE releaser bupropion increase 5-HT neuronal firing by enhancing NE release on α1-adrenoceptors located on dorsal raphe neurons [36], [20]. The selective NE reuptake inhibitor (NRI) reboxetine enhances NE transmission by selectively blocking the reuptake of NE, but also increases the tonic activation of 5-HT1A receptors in the hippocampus [75], [41].
Lithium and the 5-HT1A/β-adrenoceptor antagonist pindolol, two agents used for the potentiation and acceleration of antidepressant responses, respectively, both help SSRIs increase 5-HT neurotransmission (Fig. 1). Lithium increases 5-HT release in brain structures involved in depressive symptoms [9], such as the hippocampus and the hypothalamus, and pindolol blocks 5-HT1A autoreceptors, thus inhibiting the negative feedback produced by the rapid increase of 5-HT resulting from the blockade of 5-HT transporters [3], [7].
In this context, it is reasonable to ask if and how NK1 antagonists fit in this framework.
Although it was initially claimed that NK1 antagonists were acting independently of the 5-HT system in depression, subsequent laboratory studies have consistently put into evidence a desensitization of 5-HT1A autoreceptors [67], [29]. It remains to be determined, however, what happens at the postsynaptic level, whether NK1 antagonists are able to potentiate postsynaptic 5-HT responses like TCAs, as well as to enhance the tonic activation of forebrain 5-HT1A receptors.
Another action of antidepressants is to regulate NE transmission (Fig. 2, Table 2). However, different classes of antidepressants exert dissimilar acute and chronic effects on NE transmission. SSRIs do not change NE firing activity acutely, but decrease this parameter after a chronic treatment. The 5-HT/NE dual reuptake inhibitor (SNRI) venlafaxine, MAOIs and most TCAs decrease NE firing activity after both acute and chronic administration [76]. Similarly, the α2-adrenergic antagonist mirtazapine increases NE firing activity after chronic treatment [10], [36]. This enhancing action of mirtazapine may appear discordant with the effect of other antidepressants drugs on locus coeruleus NE neuron firing, but it is important to emphasize that it is limited in amplitude, and much more pronounced on 5-HT neurons. Nevertheless, in projection areas the impact of mirtazapine on the synaptic availability of NE is expected to be an enhancement, resulting from a small increase in firing in the presence of antagonized terminal α2-adrenergic autoreceptors. Similarly, selective NE reuptake inhibitors, like desipramine and reboxetine, desensitize these terminal α2-adrenoceptors and increase synaptic NE availability in the presence of NE reuptake inhibition, despite a sustained and diminished firing activity of NE neurons [83], [76], [41]. As well, MAOIs enhance synaptic NE availability in postsynaptic structures despite a persistently attenuated firing activity [26].
It may appear paradoxical that synaptic levels of NE can be enhanced in the presence of decreased NE neuronal firing. However, microdialysis studies have shown that this is truly the case, most likely because this system—unlike the 5-HT one—may be more dependent on its terminal autoreceptors to modulate synaptic availability of NE than its cell body autoreceptors. It may also appear problematic that increasing NE transmission may be beneficial in anxiety disorders, like panic disorder, and in depression when significant anxiety is present. These neurobiological observations may first be reconciled with the abovementioned clinical phenomena by considering that most noradrenergic antidepressants desensitize β-adrenoceptors, which mediate an excitatory influence on neuronal electrical activity [48]. Second, the sustained attenuation of the firing activity of NE neurons, by either noradrenergic antidepressants or even SSRIs, would dampen sudden increases in NE neuronal firing resulting from anxiogenic or even panicogenic stimuli.
Third, during a stress period lasting several weeks, adrenergic regulation changes, giving an initially high level and then finally a low level of noradrenaline associated with an initial down-regulation of α2-adrenoceptors followed by an up-regulation [28]. Taken together, these data help to explain why a potent NE reuptake inhibitor, like desipramine or reboxetine, may be beneficial even in a condition like panic disorder or severe depression.
Patients with depression may have structural as well as functional abnormalities in limbic-thalamic-cortical networks, which are hypothesized to modulate mood states in human. A core area in these networks is the hippocampus. A decrease of the hippocampal volume has been observed in a significant number of studies in depression [81]. The hippocampus is richly innervated by 5-HT and NE projections that course along three common bundles of fibers: the fimbria-fornix, the fasciculus cinguli and the amygdaloid pathways. All NE fibers in these bundles arise from locus coeruleus, 5-HT fibers originate from both nuclei of raphe medialis and raphe dorsalis. A wide variety of 5-HT and NE receptors are present in the hippocampus, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 subtypes (for a review see [58]). Electrophysiological investigations carried out in our laboratory have documented that certain long-term antidepressant treatments work by increasing NE neurotransmission and, in parallel, enhancing 5-HT neurotransmission in rat CA3 hippocampus by different mechanisms (for review see [10], [58]).
Nevertheless, from microdialysis studies, it is not clear if the release of NE and 5-HT is a common pathway for all types of antidepressants. Chronic, but not acute, treatment with the SSRI paroxetine increases the release of both 5-HT and NE in ventral hippocampus [38], but the same results were not replicated with the SSRI sertraline, that increases NE release in the cerebral cortex but not hippocampus [78]. Chronic treatment with the NRI reboxetine increases NE release in the cerebral cortex [41].
Two major changes incontestably occur in hippocampus after chronic treatment with antidepressants: (1) an increased tonic activation of 5-HT1A postsynaptic receptors; and (2) neurogenesis (Table 3). After long-term treatment with the TCA imipramine, the SSRI paroxetine, the reversible MAO-A inhibitor befloxatone, the α2-adrenergic antagonist mirtazapine, the 5-HT1A receptor agonist gepirone and repeated electroconvulsive shocks, there is an increased tonic activation of postsynaptic 5-HT1A receptors. This was documented using the selective 5-HT1A receptor antagonist WAY 100635 that markedly increased the firing activity of CA3 pyramidal neurons following such antidepressant treatments. Such a disinhibition was absent in rats treated with the antipsychotic drug chlorpromazine, and in rats receiving a single or multiple electroconvulsive shocks in combination with an intra-hippocampus pertussis toxin pretreatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of hippocampus postsynaptic 5-HT1A receptors [37]. This result was replicated also using the NRI reboxetine [75].
New theories are beginning to consider major depression as a disturbance of neural plasticity, in which the neurogenesis and a loss of plasticity in hippocampus play a fundamental role [51], [22], [52], [42]. Antidepressants and mood stabilizers, by acting at the hippocampal level, seem to reverse and protect against this loss of plasticity [52], [68]. In particular, chronic but not acute treatment with the MAOI tranylcypromine, reboxetine and ECT increases the number of BrdU-positive cells in the dentate gyrus; ECT and fluoxetine treatment also increase hippocampus cell proliferation of new neurons [51]. Neurogenesis appears to be implicated in the behavioral effects of antidepressants. In fact, disrupting antidepressant-induced neurogenesis in hippocampus blocks behavioral responses to antidepressants [68]. Moreover, 5-HT1A receptor null mice are insensitive to the neurogenesis and behavioral effects of fluoxetine, confirming the importance of 5-HT1A hippocampus receptors in mediating the effects of antidepressant drugs and their essential role in the regulation of antidepressant-induced neurogenesis [68].
It may be postulated that SSRIs tonically activate 5-HT1A hippocampus receptors that, in turn, initiate the cascade of neuroplasticity and neurogenesis events. In particular, 5-HT1A receptors activate the kinase Ca 2+/calmoduline-dependent kinase and mitogen-activated protein (MAP) kinase, that increase the function and expression of CREB, one of the major transcription factor controlling neurotrophic factors [21]. However, more research is needed to better understand the processes that link all classes of antidepressants to postsynaptic 5-HT1A receptors as well as the intracellular cascade leading to neuroplasticity in hippocampus.
Section snippets
Substance P receptors in the central nervous system
The neuropeptide substance P is a member of the tachykinin family of peptides and is involved in various biological functions including pain perception, neurogenic control of inflammation and regulation of the activity of other neurotransmitters. SP exerts its functions by binding mainly to the NK1 receptor. Two additional mammalian tachykinins have been identified [56]: neurokinin A and neurokinin B that exhibit, respectively, affinity for the NK2 and NK3 receptors.
It is important to note that
NK1 receptors and 5-HT system
The major source of 5-HT projections to forebrain is the nucleus of dorsal raphe (DR). NK1 receptors are abundantly present in mouse DR, but are then expressed in non-serotonergic neurons [67]. In the rat DR, dendrites containing NK1 receptors are selectively distributed in the dorsomedial subdivision. The majority of these dendrites did not display immunoreactivity for the 5-HT-synthesizing enzyme tryptophan hydroxylase [15]. It is important to mention, however, that Lacoste et al. [47] have
NK1 receptors and NE system
NK1 receptors are widely expressed in the locus coeruleus [14] and notably on the soma of its NE neurons [67]. Haddjeri and Blier [34] demonstrated that the acute systemic administration of the relatively weak NK1 antagonists, WIN 51708 and CP-96,345, did not modify noradrenergic firing, but attenuated the suppressant effect of the α2-adrenoceptor agonist clonidine, suggesting that these drugs affected the NE system via an attenuation of the function of α2-adrenoceptors on the cell body of NE
Effects of NK1 antagonists and SP on hippocampal neurons
NK1 antagonists seem to share several properties in hippocampus with other antidepressant classes (Table 3). Millan et al. [57], using the microdialysis technique, observed that acute treatment with GR 205171 increased dialysate levels of NE in the dorsal hippocampus. The combination—but not the single administration—of GR 205171 or L-733060 with SSRIs potentiated the effects of SSRIs on 5-HT release in cortical areas [32], suggesting that NK1 antagonists could potentiate the antidepressant
Conclusion
Based on the current literature, it seems clear that NK1 antagonism enhances 5-HT and NE transmission via presynaptic mechanisms, in a manner similar but not identical to that of various classes of antidepressants. NK1 antagonists increase the firing of 5-HT and enhance the burst activity of NE neurons, possibly resulting in an increase of NE release in some brain regions. The effects of these compounds on the activation of postsynaptic 5-HT1A receptors, the increase of 5-HT release when
Acknowledgement
G.G. received a scholarship from Fonds de la Recherche en Santé du Québec (FRSQ).
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