Current Pharmaceutical Design, 2009, 15, 1647-1674 1647
`1381-6128/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.
`Tachykinin Receptors as Therapeutic Targets in Stress-Related Disorders
`Karl Ebner*, Simone B. Sartori and Nicolas Singewald
`Department of Pharmacology and Toxicology, Institute of Pharmacy, and Center for Molecular Biosciences Innsbruck
`(CMBI), University of Innsbruck, Austria
`Abstract: The first report demonstrating the therapeutic efficacy of an orally applied neurokinin-1 (NK1) receptor an-
`tagonist in depression was published 10 years ago. Although there were difficulties to reproduce this particular finding, a
`huge amount of data has been published since this time, supporting the potential therapeutic value of various tachykinin
`ligands as promising novel tools for the management of stress-related disorders including anxiety disorders, schizophrenia
`and depression. The present review summarizes evidence derived from anatomical, neurochemical, pharmacological and
`behavioral studies demonstrating the localization of tachykinin neuropeptides including substance P (SP), neurokinin A,
`neurokinin B and their receptors (NK1, NK2, NK3) in brain areas known to be implicated in stress-mechanisms,
`mood/anxiety regulation and emotion-processing; their role as neurotransmitters and/or neuromodulators within these
`structures and their interactions with other neurotransmitter systems including dopamine, noradrenaline and serotonin (5-
`hydroxytryptamine, 5-HT). Finally, there is clear functional evidence from animal and human studies that interference
`with tachykinin transmission can modulate emotional behavior. Based on these findings and on evidence of upregulated
`tachykinin transmission in individuals suffering from stress-related disorders, several diverse tachykinin receptor antago-
`nists, as well as compounds with combined antagonist profile have been developed and are currently under clinical inves-
`tigation revealing evidence for anxiolytic, antidepressant and antipsychotic efficacy, seemingly characterized by a low
`side effect profile. However, substantial work remains to be done to clarify the precise mechanism of action of these com-
`pounds, as well as the potential of combining them with established and experimental therapies in order to boost efficacy.
`Key Words: Substance P, NKA, NKB, neurokinin, tachykinin, NK1 receptor, NK2 r eceptor, NK3 receptor, depression, anxi-
`ety, panic, schizophrenia, antidepressant, anxiolytic, stress, multi target approach.
`1. INTRODUCTION
`Mammalian tachykinins (neurokinins) including the three
`main members substance P (SP), neurokinin A (NKA) and
`neurokinin B (NKB) are a group of neuropeptides which
`share a common carboxy-terminal amino acid sequence,
`Phe-X-Gly-Leu-Met-NH2, where X is a hydrophobic residue
`that is either an aromatic or a beta-branched aliphate [1, 2].
`The three peptides are almost exclusively expressed in neu-
`rons and act as neurotransmitters and/or neuromodulators in
`the central nervous system [3]. More recently, a novel pep-
`tide was discovered which was termed hemokinin 1 because
`it was detected primarily in hematopoietic cells [2]. How-
`ever, although this tachykinin has also been detected in the
`central nervous system, at least in the mouse brain [4], its
`neurotransmitter/neuromodulator function is not established
`so far. In contrast, other tachykinin-like peptides such as
`endokinins are localized and exert their effects mainly in the
`periphery [5, 6].
` The tachykinins are encoded on three different genes,
`termed TAC1 (formerly preprotachykinin A, PPT-A), TAC3
`(formerly PPT-B) and TAC4 (formerly PPT-C). SP and
`NKA are encoded by TAC1 [7], which produces four splice
`*Address correspondence to this author at the Department of Pharmacology
`and Toxicology, Leopold-Franzens-University of Innsbruck, Peter Mayr-
`Str.1, Innsbruck A-6020, Austria; Tel: +43 512 507 5623; Fax: +43 512 507
`2760; E-mail: karl.ebner@uibk.ac.at
`variants of exon 6:
- and -TAC1 yielding SP alone and  -
`and -TAC1 producing SP along with NKA [8-11]. Interest-
`ingly, species-dependent differential expression of TAC1
`splice variants has been observed. For example, in the rat ß
`and -TAC1 mRNA are most abundant [12] suggesting that
`in many cases SP and NKA are synthesized together and
`released as co-transmitters. In contrast, NKB and HK-
`1/endokinins are generated from separate genes, TAC3 and
`TAC4, respectively [13-15].
`1.1. Distribution of Tachykinins in the Central Nervous
`System
`Most studies on the central distribution of the tachykinins
`have been carried out in the rat brain and have primarily fo-
`cused on SP. By using immunohistochemical and in-situ
`hybridisation methods a widespread distribution of SP has
`been found in the mammalian brain. In various species, high
`levels of SP-immunoreactive cell bodies, fibres and termi-
`nals have been identified in many forebrain, midbrain and
`brainstem areas implicated in the modulation of stress, anxi-
`ety and mood responses such as the cingulate cortex, caudate
`putamen, nucleus accumbens, septum, hippocampus, amyg-
`dala, various hypothalamic areas as well as periaqueductal
`gray, dorsal raphe nucleus, locus coeruleus, various parabra-
`chial nuclei and in the nucleus of the tractus solitarius [16-
`19]. Specifically, the extensive distribution of SP in limbic
`brain structures such as amygdala, septum and bed nucleus
`of the stria terminalis [16, 17, 20, 21] led to the conclusion
`HELSINN EXHIBIT 2057
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
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`1648 Current Pharmaceutical Design, 2009, Vol. 15, No. 14 Ebner et al.
`that the SP system may play an important role in emotional
`and affective functions. In these regions, SP frequently coex-
`ists in the same neuron with other neuropeptides including
`neurokinins and with ‘classical’ neurotransmitters such as
`dopamine (DA), acetylcholine, serotonin (5-hydroxytrypt-
`amine, 5-HT), noradrenaline (NA), glutamate or GABA sug-
`gesting an important role as co-transmitter [22-24] (see chap-
`ter 1.5). In respect to affective disorders such as depression
`and anxiety disorders the colocalization with brain seroton-
`ergic and noradrenergic systems are of high relevance be-
`cause these monominergic systems are known to be involved
`in the regulation of emotions including mood. Studies on the
`distribution of SP in the human brain have shown consider-
`able similarity to that in the rat brain with particular dense
`distributions of immunoreactive fibres or neurons containing
`SP in cortical and hypothalamic areas, in the hippocampus,
`substantia nigra and brain stem areas [25-29]. However, de-
`spite this similarity there are also some species differences.
`For example, SP seems to be more abundant in human corti-
`cal and hippocampal areas compared to the rat brain [30, 31]
`indicating an increased SP involvement in higher brain func-
`tions with increasing phylogenetic complexity. Also in re-
`spect to colocalisation with other neurotransmitter systems
`species differences were found. For example, lower level of
`colocalisation of SP and 5-HT were detected in the dorsal
`raphe nucleus of rats compared to that of humans and mon-
`keys [32-34]. However, the physiological significance of
`such species differences are not well documented.
` Compared to SP, the other tachykinins have generally
`been found in lower concentrations in the central nervous
`system. As expected, NKA is highly co-localized with SP
`due to its derivation from the same precursor gene (see in-
`troduction). However, tissue measurements suggest that the
`ratio between these tachykinins can vary throughout several
`brain regions. For instance, in the striatum or substantia ni-
`gra the SP concentration is several times higher than that of
`NKA while in other areas such as hippocampus this ratio
`seems to be more balanced [35]. Nevertheless, it should be
`noted that using different antisera or extracts of distinct brain
`punches (e.g. subregions of a brain area) may provide differ-
`ent results as for example, even higher NKA concentrations
`(relative to SP) have been found in several regions such as
`frontal cortex, hippocampus and nucleus accumbens [36,
`37]. Based on considerable variances between such studies
`and methodological limitations concerning tissue measure-
`ments quantitative comparisons should be interpreted with
`caution.
` The distrubution of NKB, generated from TAC3 mRNA
`is different to that of SP and NKA. Neurons containing NKB
`immunoreactivity and precursor mRNA are present in the
`olfactory bulb and tubercle, some cortical regions, nucleus
`accumbens, hi ppocampus, septum, bed nucleus of stria ter-
`minalis, several hypothalamic regions, amygdala, medial
`habenula, periaqueductal gray, superior and inferior collicu-
`lus, substantia nigra and nucleus of the spinal trigeminal tract
`[38-41]. Although the distribution of NKB does overlap with
`that of SP, there are also some striking differences. For ex-
`ample, in the nigro-striatal system or in the raphe nuclei nu-
`merous SP labelled cells were found, while NKB labelling
`was very low [40]. On the other hand, in the hippocampus
`where only moderate amounts of SP were found at least in
`rats [42] the concentration of NKB seems to be very high
`[39]. Moreover, there are also examples for a distinct and
`complementary distribution pattern of SP and NKB neurons
`within a particular brain region such as the human hypo-
`thalamus where NKB was primarily found in the rostral hy-
`pothalamus, whereas SP predominated in the posterior hypo-
`thalamus [25]. Notably, there is also some evidence for a
`species difference in the NKB expression. In a very recent
`study it was shown that NKB and NK3 r eceptor expression
`in mice and rats are in part divergent [43]. For example, in
`the hippocampus of rats NKB has been found in the granular
`layer of the dentate gyrus, while in mice no such expression
`was found although NK3 r eceptor expression in this area
`was congruent in mice and rats [43]. These results might
`have implications for the interpretation of behavioral results
`concerning the NKB/NK3 receptor system in these species
`(see section 2.1.2).
`1.2. Tachykinin Binding Sites: Classification and Charac-
`teristics
` The biological effects of tachykinins are mediated
`through a family of seven transmembrane domain G-protein
`coupled receptors. The interaction of the tachykinins with
`their preferred receptor results in an elevation of intracellular
`Ca
`2+ via a phospholipase C, inositol trisphosphat and diacyl-
`glycerol signalling cascade [44]. In addition, the stimulation
`of adenylate cyclase and the increase of cyclic adenosine
`monophosphate has been reported after tachykinin receptor
`activation [45]. So far, three types of neurokinin receptors
`have been identified in mammals, neurokinin-1 (NK1), neu-
`rokinin-2 (NK2) and neurokinin-3 (NK3) receptors [46, 47].
`The NK1 and NK3 binding sites are widely distributed in the
`mammalian brain whereas NK2 receptors are observed only
`in a few particular areas (see section 1.3, Fig. ( 1)). Although
`all endogenous neurokinins possess limited selectivity and,
`thus, can interact with all three receptor types, SP exhibits
`high affinity to the NK1 receptor, whereas NKA and NKB
`preferentially bind to the NK2 and NK3 receptors, respec-
`tively [2, 46-48]. This cross-talk among the three receptor
`types may, indeed, be of importance in pathophysiological
`states when tachykinin levels are thought to be exaggerated
`rather than during physiological conditions. A further com-
`plication is the proposal of different binding sites on the
`NK1 receptor, including the “classic” NK1 receptor binding
`site with high affinity for SP and low affinity to NKA and
`NKB, the “septide-sensitive” NK1 receptor site [49] where
`in addition to SP also NKA, NKB and some SP fragments
`(e.g. SP 6-11) bind with high affinity and finally a “new
`NK1-sensitive binding site” [5]. Species-dependent variation
`of the amino acid sequence of the NK1 receptor protein [50,
`51] underlying different receptor pharmacology [52] has
`been noted. Although these variations do not affect the affin-
`ity of endogenous SP, however, they determine the species-
`related differences in the potency of non-peptide antagonists
`[50, 51], which is thought to be due to different binding epi-
`topes on the NK1 receptor for SP and antagonists [53].
`1.3. Distribution of Tachykinin Receptors in the Central
`Nervous System
` The regional distribution of tachykinin receptors in the
`central nervous system has been studied in several species.
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`Tachykinin Receptors as Therapeutic Targets Current Pharmaceutical Design, 2009, Vol. 15, No. 14 1649
`Autoradiographic and immunohistochemical studies have
`shown a widespread distribution of tachykinin receptors
`throughout the mammalian brain and have identified NK1
`and NK3 receptor binding sites in higher densities than NK2
`receptor sites [46]. While NK1 and NK3 receptors are
`widely distributed in the whole brain, NK2 receptors are
`only found in few structures including several cortical areas,
`hippocampus, nucleus accumbens, parts of the thalamus and
`lateral septum [16, 54]. The presence of NK2 receptor bind-
`ing sites in several limbic structures is consistent with a pos-
`sible role of this receptor type in the modulation of emo-
`tional processes (Fig. ( 1)). Similarly, also NK1 and NK3
`receptors have been identified in brain areas i nvolved in the
`control of anxiety and stress responses such as the prefrontal
`cortex, hippocampus, caudate putamen, septum, amygdala
`and various thalamic and hypothalamic nuclei, as well as
`periaqueductal gray, habenula, dorsal raphe and locus coer-
`uleus
` [16, 17, 54-56] (Fig. (1)). Despite considerable overlap
`in some of these areas there are marked differences in distri-
`bution patterns, in particular, in specific subregions between
`these receptor types. For example, in the amygdala a strong
`NK1 receptor expression is found in the medial and cortical
`part extending into the basomedial part while NK3 receptors
`are present mainly deep in the basomedial and basolateral
`part [16, 54]. Similarly, in the septum NK1 receptors are
`abundant in both its lateral and medial parts [57] whereas
`NK3 receptors are almost exclusively expressed in its medial
`part [55]. Nevertheless, the greatest differences in NK1 and
`NK3 receptor distribution are evident in hypothalamic re-
`gions where NK3 receptors are more prominent than NK1
`receptors [54] and (prefrontal) cortical regions where NK3
`receptors are present in superficial and deep layers and NK1
`receptors are more restricted to the upper cortical layers [58,
`59]. Besides, there is also some evidence for interspecies
`differences in the expression of tachykinin receptors, in par-
`ticular, in the hippocampus and cortex suggesting that these
`receptors mediate different functions in different species [58,
`60, 61]. For instance, in cortical areas of the human but not
`rat brain NK3 receptors are found in high density on astro-
`cytes [58, 59]. In contrast, in rats tachykinin receptors are
`expressed on glia cells in the brain of newborn animals only
`whereas in older animals these receptors are localised exclu-
`sively on neurons [62].
` Although in most of these areas there is good accordance
`between the distribution of tachykinin peptide containing
`fibers and respective binding sites, an interesting aspect is an
`apparent mismatch between receptors and endogenous
`ligands in some areas. Most notably is the substantia nigra,
`where the concentration of SP is extremely high, but the ex-
`pression of NK1 receptors is very low [17, 19]. A partially
`reversed situation seems to exist in the dorsal hippocampus
`with low SP levels and high densities of NK1 receptor bind-
`ing sites [16]. Reasons for such mismatches may be (i) tech-
`nical factors, (ii) the existence of yet undiscovered subtypes
`of neurokinin receptors [63] and (iii) their neuromodulatory
`character, i.e. that tachykinins can diffuse over long dis-
`tances to bind to their receptors (volume transmission) [64,
`65] making a direct relationship between the density of
`ligand innervation and the density of post-synaptic NK re-
`ceptors not obligatory. Finally, since tachykinins can bind at
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`Fig. (1). Schematic drawing demonstrating the distribution and relative density of NK1, NK2 and NK3 receptors in rodent brain areas asso -
`ciated with emotional processing. Abbreviations: AMY, amygdala; BNST, bed nucleus of the stria terminalis; DR, dorsal raphe; FC /PFC,
`frontal/prefrontal cortex; HB, habenula; HC, hippocampus; HTH, hypothalamus; IP, interpedincular nucleus; LC, locus coeruleus; NAcc,
`nucleus accumbens; NTS, nucleus tractus solitarius; OB, olfactory bulb; PAG, periaqueductal gray; PBN, parabrachial nucleus; SE P, septum;
`TH, thalamus. Data from references [16, 17, 54, 55].
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`1650 Current Pharmaceutical Design, 2009, Vol. 15, No. 14 Ebner et al.
`all three receptors, it may be speculated that under specific
`conditions (e.g. in stressed or pathophysiologically altered
`systems) the concentrations of distinct tachykinin peptides
`are high enough to activate other than the preferred tachyki-
`nin receptors.
`1.4. Autoregulation of Tachykinin Transmission
` Although
` data are limited and mainly concern the somato-
`sensory system, the existence of a NK1 autoreceptor has
`been suggested [66], opening one direct possibility of a
`presynaptic automodulation of SP transmission. Both inhibi-
`tory and stimulatory actions of putative NK1 autoreceptors
`have been proposed. In the spinal cord it has been shown that
`the NK1 receptor antagonists RP67580 and SR140333
`increase electrically evoked in vitro SP release from slices
`[67], which was taken as evidence for the existence of an
`inhibitory NK1 autoreceptor, since NK1 receptors are not
`present on inhibitory neurons such as GABAergic neurons in
`the investigated part of the spinal cord [66]. Unfortunately,
`data on possible autoregulation in supraspinal, in particular
`limbic areas are scarce. In our recent work we were able to
`provide some evidence for such an autoregulatory mechan-
`ism in the amygdala of the rat. By infusing a selective NK1
`receptor anta gonist locally into the medial amygdala, SP
`release is increased in this brain area suggesting a self-regu-
`latory capacity of SP-mediated neurotransmission [68].
`Although some anatomical evidence for a presynaptic locali-
`zation of NK1 receptors on SP-containing terminals has been
`gained in distinct brain areas such as nucleus accumbens,
`periaqueductal gray and striatum [69-72], we could not
`detect a presynaptic localization of NK1 receptors on SP-
`containing terminals in the medial amygdala [68]. Hence, the
`observed inhibitory feedback regulation of SP release in this
`area most likely involves interaction with inhibitory neurons
`and neurotransmitter systems (e.g. GABAergic; see section
`1.5). Interestingly, this inhibitory autoregulation of SP via
`NK1 receptors was not evident during an applied stressor
`disproving the idea that it may serve as a safety response
`aimed at preventing overstimulation. In contrast, it seems
`that in the medial amygdala the activation of NK1 receptors
`is further faciliated by endogenous SP in response to a stress-
`ful experience since NK1 receptor blockade stereoselectively
`reduced stress-induced SP release [68]. Thus, this self-regu-
`latory capacity of SP-mediated neurotransmission differs
`under basal and stimulated/stressful conditions. Although the
`exact mechanisms underlying this effect are yet poorly
`understood, the further facilitation of stress-induced SP
`release may have important functional consequences via
`involvement of other tachykinin receptors in addition to NK1
`such as NK2 and NK3 receptors which are also thought to
`play a role in the modulation of depression- and anxiety-like
`behavior (see section 2.1.2). Further studies should clarify
`the physiological and behavioural role of these receptors and
`their interaction in the amygdala during stressful situations.
`1.5. Interaction of Tachykinins with Other Neurotrans-
`mitter Systems
`
`Interaction with Amino Acids
` Similar to most other neuropeptides, tachykinins widely
`coexist with classical neurotransmitters (see section 1.1).
`Moreover, it is well documented that intracerebral admini-
`stration of tachykinins or adequate agonists can modulate the
`release of a number of neurotransmitters including acetyl-
`choline, monoamines and amino acids indicating potential
`interaction of tachykinins with these neurotransmitter sys-
`tems. In the cortex, for example, NK1 receptor activation
`promotes the release of GABA at synapses of principal neu-
`rons pointing towards a possible inhibitory role onto pyrami-
`dal output neurons [73]. This inhibitory effect on principal
`neurons does not seem to be mediated by a direct, but likely
`through an indirect effect via activation of inhibitory in-
`terneurons. Indeed, a dense expression of NK1 receptors on
`GABAergic interneurons within cortical areas is reported
`[74]. On the other hand, NK1 receptor activation has also
`been shown to excite cortical neurons possibly via activation
`of glutamate-containing interneurons resulting in an in-
`creased glutamate release [75]. Similar excitatory effects
`were found after NK3 r eceptor activation in the prefrontal
`cortex of guinea pigs [76] and cingulate cortex of gerbils
`[77]. In other forebrain areas such as hippocampus and
`amygdala tachykinins may regulate the synaptic input to
`principal neurons by increasing the excitability of GABAer-
`gic interneurons [78-80]. For example, in the basolateral
`amygdala of rats and guinea pigs NK1 receptors are largely
`restricted to GABA containing interneurons [79, 81] and
`NK1 receptor activation has shown to stimulate inhibitory
`synaptic transmission in vitro [79]. Similar to the NK1 re-
`ceptor, the other two tachykinin receptors have been reported
`to modulate GABAergic transmission in various brain areas.
`For example, depending on the brain area activation of NK3
`receptors can reduce [82] or enhance GABA release [83].
`Interaction with Serotonin
` There is also evidence for functional interaction between
`tachykinins and monoaminergic systems including the 5-HT
`and NA system which both are known to be implicated in the
`pathophysiology and treatment of mood disorders [84, 85].
`First evidence for such a functional interaction comes from
`anatomical studies demonstrating high density of tachykinin
`receptors (e.g. primarily NK1 receptors) in m onoaminergic
`nuclei such as dorsal raphe nucleus and locus coeruleus (see
`section 1.3). However, although NK1 r eceptors have been
`identified on serotonergic and noradrenergic cells suggesting
`a direct influence on the firing activity of monoaminergic
`neurons, the exact mechanisms by which tachykinins influ-
`ence 5-HT and NA neurons are not completely understood.
`For instance, in the dorsal raphe nucleus several mechanisms
`have been proposed through which NK1 receptors affect the
`firing rate of 5-HT neurons (see section 3.1.1). Electrophysi-
`ological studies have shown that NK1 receptor blockade,
`either by antagonist treatment or by genetic disruption, in-
`creases the firing of dorsal raphe neurons and therefore re-
`sults in enhanced serotonergic neurotransmission [86]. Based
`on these findings it has been proposed that the antidepressant
`effects of NK1 receptor antagonists may result from an in-
`creased central 5-HT transmission similar to that of estab-
`lished antidepressants such as selective serotonin reuptake
`inhibitors (SSRIs). However, despite these similarities, clear
`differences exist between mechanisms of action of SSRIs
`and NK1 receptor antagonists. For instance, SSRIs require
`prolonged administration for a significant clinical improve-
`ment. This delay is thought to be caused by compensatory
`changes resulting in a desensitization of somatodendritic 5-
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`Tachykinin Receptors as Therapeutic Targets Current Pharmaceutical Design, 2009, Vol. 15, No. 14 1651
`HT1A autoreceptors in the dorsal raphe nucleus following
`chronic SSRI administration and a delayed increase in 5-HT
`release in dorsal raphe projection fields [87]. In contrast,
`NK1 receptor anta gonists may have a faster onset of 5-HT
`related therapeutic effects, because they exert their effects
`not exclusively by an attenuation of somatodendritic 5-HT
`1A
`autoreceptor responsiveness [88], opening the possibility of
`faster increases in 5-HT release (see section 3.1.1). Indeed,
`we found increased 5-HT release in the lateral septum, an
`important dorsal raphe terminal region involved in emotional
`processing [89] after acute intraseptal NK1 receptor block-
`ade [57]. Specifically, administration of the selective NK1
`receptor anta gonist L822429 locally into the lateral septum
`reversed the stress-induced decrease of extracellular septal 5-
`HT efflux coinciding with a reduction of depression-like
`behavior (Fig. ( 2)). Interestingly, we found similar effects
`also after a single systemic administration [57]. Thus, our
`data suggest that NK1 receptor antagonists can elicit an im-
`mediate, functionally significant facilitatory effect on 5-HT
`transmission locally in a terminal region of 5-HT neurons
`without a direct involvement of the interaction with neuronal
`firing at the cell body level of raphe neurons.
`Interaction with Noradrenaline
` In addition to alterations in 5-HT neuronal function, there
`is also evidence that tachykinins modulate the firing charac-
`teristics of ascending NA neurones originating in the locus
`coeruleus. These neurones are innervated by tachykinin-
`containing fibres and tachykinin receptors, mainly NK1 and
`NK3 receptors, are highly expressed in this brain area (see
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`Fig. (2). Effects of NK1 receptor antagonism within the lateral septum on 5-HT release and stress-coping behavior of rats during forced
`swimming. (A) Schematic representation of the experimental set-up of the microdialysis study demonstrating the infusion of the NK1 recep-
`tor antagonist L822429 locally into the lateral septum (prominent terminal area of serotonergic dorsal raphe neurons) with conc omitant
`measurements of extracellular 5-HT levels. ( B) Intraseptal NK1 receptor blockade reverses the stress-induced decrease of extracellular 5-HT
`levels in the lateral septum. ( C) Improved stress coping after intraseptal application of L822429. Note the effects of L822429 are selectively
`mediated by NK1 receptors since its less active enantiomer had no effect. Adapted, with permission, from reference [57].
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`section 1.3). Moreover, it is well documented that NK1 and
`NK3 receptor ligands m odulate the firing rate of locus coer-
`uleus neurons [90-95]. Microdialysis studies in freely mov-
`ing animals have shown that NK1 receptor antagonists in-
`crease NA release in terminal fields of the locus coeruleus
`such as prefrontal cortex and hippocampus [95, 96]. Interest-
`ingly, this facilitatory effect of NK1 receptor blockade on
`NA release was more pronounced than that on 5-HT and can
`be observed even after acute treatment (see section 3.1.1).
`Similarly, NK1 receptor knockout mice also show increased
`firing rate of locus coeruleus neurons [86] and a higher basal
`NA efflux in the prefrontal cortex than wild type controls
`[97, 98]. Notably, all these studies have investigated the ef-
`fects of NK1 receptor activation or blockade on noradrener-
`gic transmission under basal conditions. However, informa-
`tion regarding the effects of such interactions during situa-
`tions where tachykinin pathways are highly activated, such
`as during aversive and stressful situations [99] would be
`even more relevant from a functional point of view. This
`issue seems particularly interesting as stress represents an
`important pathogenetic factor in many psychiatric disorders
`(see 2.1.1), and tachykinin antagonists have been shown to
`be particularly effective on “stressed” or pathophysiologi-
`cally deranged systems [99, 100, see section 2.2.3]. Moreo-
`ver, one should take into consideration that regulation of
`basal and evoked neurotransmitter release in a particular
`brain region may differ quantitatively and/or qualitatively,
`and effects on basal release may not generalize to effects on
`activated systems [101]. Indeed, we recently obtained evi-
`dence for such different modulation of NA release after NK1
`receptor blockade as the administration of the selective NK1
`receptor anta gonist L822429 into the locus coeruleus en-
`hanced basal, but attenuated stress-induced NA release in the
`prefrontal cortex [96]. Notably, similar attenuating effects on
`stress-induced NA release within the prefrontal cortex were
`also found after acute systemic administration of another
`NK1 receptor anta gonist GR205171 [102]. Thus, these re-
`sults suggest that therapeutic efficacy of NK1 receptor an-
`tagonists might be mediated by a suppressant rather than a
`stimulatory effect on stress-induced hyperactivation of NA
`neurotransmission.
`Interaction with Dopamine
` The localisation of tachykinin receptors on DA cells in-
`dicates possible interaction with DA function. Neurochemi-
`cal studies have shown that in particular NK3 receptors have
`a modulatory influence on DA neurotransmission making
`this receptor a promising target for the development of novel
`antipsychotic drug therapy (see section 2.2.3) [103]. For ex-
`ample, local administration of the NK3 receptor agonist
`senktide into the ventral tegmental area and substantia nigra
`pars compacta enhanced extracellular DA efflux throughout
`their respective target areas, such as the nucleus accumbens,
`prefrontal cortex and striatum [104]. Similarly, electrophysi-
`ological data have demonstrated that NK3 receptor activation
`increases cell firing of midbrain DA neurons in rats and
`guinea pigs [105-107]. Moreover, agonist-stimulated cell
`firing of DA cells and subsequent DA efflux could be
`blocked by selective NK3 receptor antagonism [104, 106,
`108]. Interestingly, acute systemic administration of the NK3
`receptor anta gonist SB223412 (talnetant) also produced a
`significant increase in extracellular DA efflux in the prefron-
`tal cortex indicating a tonic inhibitory function of endoge-
`nous NKB on cortical DA release [108, 109]. However, al-
`though the mechanisms mediatiating this effect are not clari-
`fied yet it is unlikely that NK3 receptors located on DA cell
`bodies are involved in this mechanism because administra-
`tion of NK3 receptor a gonists directly to cell body areas en-
`hanced DA release. Therefore, an indirect mechanism via
`activation of inhibitory (e.g. GABAergic) interneurons
`through NK3 r eceptors is more likely [ 108, 109]. Further
`studies are needed to examine this interaction more closely.
`From a functional point of view it will be important to inves-
`tigate how NK3 receptors modulate DA release under stress
`conditions.
` A close look at the role of NK1 r eceptors on frontocorti-
`cal dopaminergic pathways reveals a more ambiguous and
`inconsistent picture. Previous studies have shown that block-
`ade of NK1 receptors by administration of the selective NK1
`receptor anta gonist GR205171 increased DA release in the
`prefrontal cortex of rats [102, 110] suggesting a tonic inhibi-
`tory influence of NK1 receptors on DA function. This was
`confirmed by electrophysiological data demonstrating a
`dose-dependent enhancement of the firing rate of ventroteg-
`mental dopaminergic neurones the major source of dopa-
`minergic input to the frontal cortex after NK1 receptor an-
`tagonism [110]. However, a direct action on dopaminergic
`neurones is unlikely as microinjections of SP directly into
`dopaminergic cell body areas increased DA turnover in the
`frontal cortex [111, 112]. Notably, in line with such a facili-
`tatory role of NK1 receptor activation are previous findings
`demonstrating an attenuation of the stress-induced DA turn-
`over in the prefrontal cortex of rats and gerbils after NK1
`receptor anta gonism [102, 113]. Thus, further studies are
`necessary to clarify the role of NK1 receptors in dopaminer-
`gic functions.
`2. THE SIGNIFICANCE OF TACHYKININ MECHA-
`NISMS IN ANXIETY, DEPRESSION AND SCHIZO-
`PHRENIA
` The rationale for an involvement of tachykinins in anxi-
`ety, depression and schizophrenia comes