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Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France (B.P.G, J.P.G, C.R., A.M.G.); Department of Anatomy and Developmental Biology, University College London, London, United Kingdom (S.P.H.); and Department of Pharmacology, Weill Medical College of Cornell University, New York, New York (M.T.)
Received for publication July 17, 2007.
Accepted for publication September 21, 2007.
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Abstract |
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 Top Abstract Materials and MethodsResults and DiscussionReferences |
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-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate ionotropic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). These data support the hypothesis that SP-induced over-activation of 5-HT1A autoreceptors within the DRN limits cortical 5-HT release. A better knowledge of the complex relationship between tachykininergic, serotonergic, and glutamatergic systems within the DRN might help better understand the pathophysiology and subsequent treatment of depression.
; Commons et al., 2002; Lacoste et al., 2006). In several species, including rodents and humans, SP distribution overlaps with that of its high-affinity NK1 receptor (Ribeiro-da-Silva and Hokfelt, 2000). Recent clinical and preclinical studies have pointed out the potential therapeutic action of SP (neurokinin 1) receptor antagonists in major depressive disorders (Kramer et al., 1998; Chahl, 2006). Data obtained from NK1 receptor knockout mice have suggested that the antidepressant-like action of NK1 receptor inactivation may result, at least in part, from an increase in central 5-HT neurotransmission through functional desensitization of 5-HT1A autoreceptors located in the DRN (Froger et al., 2001). Pharmacological arguments from wild-type mice undergoing long-term treatment with an NK1 receptor antagonist also favor this hypothesis (Guiard et al., 2005). It is noteworthy that such a desensitization of somatodendritic 5-HT1A autoreceptors resembles that induced by long-term treatment with selective serotonin reuptake inhibitors (Blier and de Montigny, 1980; Hjorth et al., 2000). Thus, the enhancement of serotonergic neurotransmission would be a common element in the antidepressant-like activity of both selective serotonin reuptake inhibitors and NK1 receptor antagonists.
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). These findings were consistent with intracerebral in vivo microdialysis experiments indicating that SP injection into the DRN in conscious rats produces a small, transient increase in hippocampal 5-HT release (by >30% for 20 min compared with vehicle control) (Gradin et al., 1992). The latter findings have been challenged recently by in vivo electrophysiological data, suggesting that the effects of SP depended on the location of the recording within the DRN, with excitation predominating in the dorsal part of the DRN and inhibition more ventrally (Valentino et al., 2003). Thus, whether 5-HT neurotransmission were increased or decreased in projection brain regions of the DRN would depend on the specific DRN subregion that projects to the serotonergic nerve terminal area studied. Based on their findings, Valentino et al., (2003) have drawn an in vivo model of SP regulation of 5-HT neuronal activity. They propose that excitation of DRN 5-HT neurons synaptically linked with glutamate neurons expressing NK1 receptors allows 5-HT release and subsequent activation of somatodendritic 5-HT1A autoreceptors. However, this theory is limited by the fact that 5-HT releasing properties of SP have yet to be demonstrated. We therefore employed both genetic and pharmacological approaches to clarify the interactions between SP and 5-HT1A autoreceptors. To better define the effects of proximal and distal intraraphe SP injection on extracellular levels of 5-HT ([5-HT]ext), we performed intracerebral in vivo microdialysis studies in awake, freely moving mice with probes implanted either in a brain region containing numerous 5-HT nerve terminals (frontal cortex, ventral hippocampus) or in the vicinity of 5-HT cell bodies in the DRN. |
Materials and Methods |
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TopAbstractMaterials and MethodsResults and DiscussionReferences |
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Microdialysis Procedure. Concentric dialysis probes were stereotaxically implanted under anesthesia (chloral hydrate, 400 mg/kg i.p.) into the frontal cortex (FC), ventral hippocampus (vH) (active length, 1.5 mm), or DRN (active length, 1.0 mm). Coordinates from Bregma (anteroposterior, lateral, ventral) were, FC, 1.6 mm, 1.3 mm, 1.6 mm, vH, -2.8 mm, 3.0 mm, 4 mm, and DRN, -4.5 mm, 0 mm, 3.5 mm. Animals were allowed to recover from surgery overnight and were continuously perfused with artificial cerebrospinal fluid (147 mM NaCl, 3.5 mM KCl, 1.26 mM CaCl2, 1.2 mM MgCl2, and 1.0 mM NaH2PO4, pH 7.4 ± 0.2) the next day. Dialysate samples were collected every 15 min for the FC and vH (flow rate, 1.5 µl/min) and every 30 min for the DRN (flow rate, 0.5 µl/min). Extracellular 5-HT levels were measured using a high-performance liquid chromatography system [limit of sensitivity 
1 fmol per sample (signal-to-noise ratio = 2)]. In each experiment, after 1 h of stabilization, four samples were collected to measure basal 5-HT values (means ± S.E.M.). The administration of pharmacological agents occurred at t = 0 and subsequent fractions were collected. SP (5–200 ng) was directly infused into the DRN [0.1 µl/min for 2 min via a microinjector (Harvard Appartus, France)], by means of a silica catheter glued to the microdialysis probe. WAY100635 (100 µM) (Guilloux et al., 2006) or 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 µM) (Tao et al., 1997) was injected via the probe after their dissolving in the artificial cerebrospinal fluid. The exact probe locations in brains were determined according to Bert et al. (2004).
Drugs. SP was obtained from Neosystem (Strasbourg, France). GR205171 was a gift from GlaxoSmithKline (Harlow, UK). WAY100635 and DNQX were purchased from Sigma-Aldrich (Saint-Quentin Fallavier, France).
Data Analysis and Statistics. Baseline levels of 5-HT were calculated by averaging the levels measured in the first four samples collected before treatment. After administration of the treatment, the 5-HT content of individual dialysate samples was measured and expressed as a percentage of the baseline mean. The summed effects of each treatment over the course were measured by determining the area under the curve (AUC; mean ± S.E.M.) values for 5-HT outflow during the 0- to 120-min period after treatment. Comparisons of the effects of the different doses of SP on extracellular 5-HT levels were performed on AUC values by using a one-way ANOVA followed by a Fisher's protected least-significant difference post hoc test. The overall effects of "drug pretreatment and treatment" as main factors was assessed by using a two-way ANOVA followed by Fisher's protected least-significant difference post hoc test when appropriate. Finally, a Student's t test was used to compare two experimental groups, in particular the effects of SP versus vehicle in NK1-/- and 5-HT1A-/- mutant mice.
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Results and Discussion |
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TopAbstractMaterials and MethodsResults and DiscussionReferences |
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). It is noteworthy that we found that the i.r. injection of the highest dose of SP (200 ng) failed to alter extracellular levels of 5-HT in the ventral hippocampus compared with the corresponding group of vehicle-treated wild-type mice (AUC values, -0.7 ± 6.2% versus 3.1 ± 5.1%, respectively; P > 0.05). It seems, therefore, that SP regulates the DRN activity in a region-dependent manner as previously proposed. A corollary of these intriguing findings is that the efferents of the DRN may differentially drive the activity of 5-HT neurons projecting to different forebrain structures, depending on whether these cells are activated or inhibited by SP (Valentino and Commons, 2005). From our neurochemical data, it can be postulated that SP inhibits the subpopulation of DRN 5-HT neurons projecting to the FC. In contrast, the lack of effect of i.r. injection of SP on extracellular 5-HT levels in the ventral hippocampus suggests that the latter region is not innervated by the DRN 5-HT neurons. This is in agreement with previous studies, which provided both anatomical and pharmacological evidence (Molliver, 1987; Kreiss and Lucki, 1994). Another possible explanation would be that the ventral hippocampus receives both types of innervations (i.e., neurons excited and inhibited by SP), leading to a blunted response. Although this would be important to address in future investigations, it is important to emphasize that the precise injection of drugs in mice is technically difficult, and we have to consider the possibility that SP diffused outside the DRN injection site. The median raphe nucleus, an adjacent area expressing NK1 receptors (Saffroy et al., 2003), is a region of interest as it sends serotonergic projections to the hippocampus. Nevertheless, in contrast to the present results, initial observations indicate that the injection of SP into the median raphe nucleus produces an excitatory effect on 5-HT turnover and probably neurotransmission in the hippocampus (Forchetti et al., 1982), strongly suggesting that, under our experimental conditions, the diffusion of SP was restricted to the DRN.
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). Pharmacological and genetic experiments were thus conducted to assess whether the above inhibitory effects of SP on cortical 5-HT release were specifically mediated by NK1 receptors. In NK1+/+ mice, the i.r. injection of SP (200 ng) did not modify cortical extracellular 5-HT levels when the potent and selective NK1 receptor antagonist GR205171 (30 mg/kg i.p.) was given 30 min before (Fig. 1, C and D). The dose of GR205171 was chosen on the basis of its capacity to block rat brain NK1 receptors in vivo (Rupniak et al., 2003). Similar results have been obtained using a genetic approach. Indeed, in contrast to NK1+/+ mice, we showed that NK1-/- mutant mice were insensitive to the i.r. injection of SP (200 ng) on cortical 5-HT release (Fig. 1, E and F). It is noteworthy that neither the pharmacological nor the genetic inactivation of NK1 receptors altered basal extracellular levels of 5-HT in the FC of the mice (Table 1; Fig. 1, D and F). These results concur with recent microdialysis experiments performed in awake mice (Zocchi et al., 2003; Guiard et al., 2004), suggesting a lack of tonic regulation of 5-HT transmission by SP. It is noteworthy that NK1 receptor antagonists have been reported to be efficient anxiolytic and antidepressant agents in several animal models (Chahl, 2006). Because SP and 5-HT coexist in a substantial part of the neuronal DRN population in human and rodent brains (Chan-Palay et al., 1978; Sergeyev et al., 1999), it is possible that 5-HT neurons may regulate the release of SP in stressful conditions (Ebner et al., 2004). Thus, the present results demonstrate that an increase in endogenous SP levels in the DRN (mimicked here by its local injection) specifically activates NK1 receptors, subsequently inhibiting cortical 5-HT neurotransmission. Additional work is now required to address how this particular effect of i.r. injection of SP affects depressive-like symptoms such as anhedonia or despair in various animal paradigms. Such studies could further support the hypothesis that the putative antidepressant activity of NK1 receptors antagonists is related, at least in part, to the blockade of SP neurotransmission within the DRN.
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Indirect involvement of Somatodendritic 5-HT1A Autoreceptors in the Cortical Effects of Intraraphe Injection of Substance P. Given that SP was described as an excitatory neuropeptide, we raised the possibility that its neurochemical effects on cortical 5-HT release might indirectly recruit an inhibitory component in the DRN. Because somatodendritic 5-HT1A autoreceptors play that role in the DRN (Hjorth et al., 2000), the i.r. injection of SP was evaluated in 5-HT1A-/- mice. In these mutant mice, SP (200 ng) failed to modify extracellular levels of 5-HT in the FC (Fig. 2, A and B). However, by using a genetic approach (e.g., constitutive disruption of 5-HT1A receptors by homologous recombination of the gene), we cannot definitively state whether presynaptic (in the DRN) rather than postsynaptic (in the FC) 5-HT1A receptors were involved in the inhibitory effects of SP on cortical 5-HT release. Indeed, evidence does exist that 5-HT1A autoreceptors located in the prefrontal cortex are involved in a distal control of DRN 5-HT neuronal activity (Celada et al., 2001). To determine whether there is a preferential activation of presynaptic 5-HT1A receptors in the SP response, the selective 5-HT1A receptor antagonist WAY100635 was perfused for 2 h into the DRN by reverse microdialysis in 5-HT1A+/+ wild-type mice as described previously (Guilloux et al., 2006). In the FC of 5-HT1A+/+ mice, pretreatment with the selective 5-HT1A receptor antagonist WAY100635 (100 µM, intraraphe), but not with the vehicle, significantly blocked the effects of SP injection (200 ng) on extracellular levels of 5-HT (Fig. 2, C and D). These results are consistent with the findings that both systemic and i.r. injection of WAY100635 attenuated the predominantly inhibitory effects of SP on the DRN 5-HT neuronal activity (Valentino et al., 2003). In marked contrast to the effects observed in the FC, we showed here for the first time that the i.r. injection of SP (200 ng) increased extracellular levels of 5-HT in the DRN compared with the vehicle-treated group in 5-HT1A+/+ mice, the latter effect being potentiated by WAY100635 (Fig. 2, E and F). The opposite effects of SP on extracellular 5-HT outflow in the DRN and FC appear to be somewhat equivocal. Nevertheless, they allowed anticipating that SP-induced decreases in cortical 5-HT release resulted from an overactivation of inhibitory 5-HT1A autoreceptors in the DRN. Previous studies in rats reported that relatively high extracellular 5-HT concentrations were required in the DRN to reduce forebrain 5-HT release through the activation of 5-HT1A autoreceptors (Romero and Artigas, 1997; Tao and Auerbach, 2000). No direct evidence supporting these observations has been provided in mice. On the contrary, in a recent study, we reported that a 2-fold decrease in extracellular 5-HT outflow in the DRN was sufficient to trigger an equivalent increase in the FC in mice (Guiard et al., 2004). Activation of DRN 5-HT1A autoreceptors in response to SP might contribute to the inhibition of cortical 5-HT release. It is noteworthy that despite evidence indicating a tonic inhibitory effect of DRN 5-HT1A autoreceptors on 5-HT neuronal activity (Haddjeri et al., 2004), we observed that neither the pharmacological nor the genetic inactivation of 5-HT1A autoreceptors altered the basal extracellular 5-HT levels in the frontal cortex and the DRN (Table 1, Fig. 2, B and D). These findings are in agreement with initial microdialysis studies performed in mice at somatodendritic (Bortolozzi et al., 2004; Guilloux et al., 2006) and terminal levels (He et al., 2001; Knobelman et al., 2001; Guilloux et al., 2006).
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; Liu et al., 2002, Commons et al., 2003). A last series of experiments was conducted to determine the putative involvement of glutamate in the neurochemical response to i.r. injection of SP. In our experimental conditions, we showed that the glutamate AMPA/kainate receptor blocker DNQX alone produced a slight but significant decrease in cortical 5-HT release in NK1+/+ mice. Despite its own effect, DNQX (10 µM, intraraphe) significantly attenuated the SP-induced decrease in cortical 5-HT levels (Fig. 3, A and B). This strongly suggests that the disinhibitory effect of the AMPA/kainate receptor antagonist could be ascribed to a specific involvement of glutamate in the SP response. In line with this assumption, the increase in 5-HT outflow induced by i.r. injection of SP (200 ng) was also blocked by DNQX (10 µM, i.r.) in the DRN in NK1+/+ mice (Fig. 3, C and D), whereas DNQX alone had no effect on DRN extracellular 5-HT levels as demonstrated previously (Tao et al., 1997; Tao and Auerbach., 2003). Based on these results, it can be postulated that increased glutamate release in the DRN would occur after i.r. injection of SP. However, it is important to emphasize that the i.r. injection of glutamate receptor agonists enhances the release of 5-HT at both somatodendritic and nerve terminals levels (Tao and Auerbach, 2000), whereas in the present study, the i.r. injection of SP-produced opposite effects in the DRN and FC. Because SP-induced stimulation of glutamate transmission in the DRN is a short-lasting effect (return to baseline 
10 min after injection; Liu et al., 2002), it is possible that we failed to detect any increases in 5-HT cortical release using intracerebral microdialysis. It is also possible that the elevated pool of extracellular 5-HT levels in the DRN of wild-type mice injected with SP did not solely originate from DRN 5-HT neuronal cell bodies or dendrites. Because the DRN receives serotonergic innervations from the other raphe nuclei (Tischler and Morin, 2003), the release of 5-HT may also result from the stimulation of AMPA/kainate receptors on serotonergic afferents in the DRN (Fig. 4). Alternative mechanisms, such as direct activation of NK1 receptors located on the 5-HT cell bodies, could also account for the inhibitory effect of SP on the serotonergic system. This hypothesis is supported by recent evidence showing that almost 30% of rats and mice DRN 5-HT neurons express NK1 receptors (Lacoste et al., 2006). Finally, NK1 receptors have been clearly identified on GABAergic neurons surrounding 5-HT cell bodies in the DRN and their activation might contribute, at least in part, toward SP-induced attenuation of cortical 5-HT neurotransmission.
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In conclusion, our neurochemical data support the idea that increased brain SP levels, specifically in the DRN, may represent an important step in the pathophysiology of depression. In these conditions, the potential antidepressant effects of NK1 receptor antagonists (Chahl, 2006) could be related to their capacity to block or prevent the reported effect of SP on cortical 5-HT transmission. However, it is important to mention that despite the great enthusiasm raised by the first placebo-controlled trials, no antidepressant or modest efficacy of NK1 receptor antagonists were reported in subsequent clinical studies, leading several pharmaceutical companies to discontinue their research program in this field (Czéh et al., 2006; Holtzheimer and Nemeroff, 2006). Additional studies are needed to further characterize the real impact of tachykinins on the 5-HT system, as well as the pathophysiology and treatments of depression. In particular, based on the present data, it can be proposed that abnormal SP neurotransmission in the DRN is involved in the inadequate response to the selective serotonin reuptake inhibitors (e.g., long delay of action and/or resistance to the treatment) in some patients. Consequently, rather than being used as monotherapy, NK1 receptor antagonists could conceivably be prescribed as augmentation agents in combination with a traditional antidepressant (Ryckmans et al., 2002; Guiard et al., 2004). This should arouse our attention for future clinical investigations.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS: SP, substance P; DRN, dorsal raphe nucleus; NK, neurokinin; 5-HT, serotonin; FC, frontal cortex; vH, ventral hippocampus; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-2-pyridinylcyclohexanecarboxamide; DNQX, 6,7-dinitroquinoxaline-2,3-dione; GR205171, N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine; AUC, area under the curve; ANOVA, analysis of variance; i.r., intraraphe.
Address correspondence to: Alain M. Gardier, Univ Paris-Sud EA 3544, Fac. Pharmacie, Chatenay-Malabry cedex F92296, France. E-mail: alain.gardier{at}u-psud.fr
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