Modulation of basal and stress‐induced amygdaloid substance P release by the potent and selective NK1 receptor antagonist L‐822429

Singewald, Nicolas; Chicchi, Gary G.; Thurner, Clemens C.; Tsao, Kwei-Lan; Spetea, Mariana; Schmidhammer, Helmut; Sreepathi, Hari Kishore; Ferraguti, Francesco; Singewald, Georg M.; Ebner, Karl

doi:10.1111/j.1471-4159.2008.05596.x

Cited by 49 publications

(46 citation statements)

References 95 publications

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“…L-822429 binds with high affinity to the rat NK1R and is highly selective for the NK1R over the NK2 and NK3 receptors, respectively. In contrast, the enantiomer demonstrates little to no binding affinity for any of the three NK receptor subtypes (Singewald et al, 2007).…”

Section: Effects Of Intraseptal and Systemic Nk1r Antagonist Administmentioning

confidence: 99%

“…In the second series of experiments, microdialysis was used to administer the selective NK1R antagonist (2S,3S)-N-{[2-cyclopropoxy-5-(5-trifluoromethyl)tetrazol-1-yl]benzyl}-(2-phenylpiperidin-3-yl)amine dihydrochloride (L-822429; Ebner et al, 2004;Singewald et al, 2007) locally into the LS. Therefore, four groups of animals implanted with a microdialysis probe into the right LS were dialyzed with aCSF at a rate of 3.3 ml/min as described above.…”

Section: Effects Of Intraseptal and Systemic Nk1r Antagonist Administmentioning

confidence: 99%

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Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Ebner

Singewald

Whittle

et al. 2007

Neuropsychopharmacol

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Antagonists of the substance P (SP) preferring neurokinin 1 receptor (NK1R) represent a promising novel class of drugs for the treatment of stress-related disorders such as depression and anxiety disorders; however, the involved neuronal pathways releasing SP in response to stressors are ill defined. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we found that exposure to forced swim stress increased SP release in the rat lateral septum (LS), a key area in processing emotions and stress responses. Acute administration of the selective NK1R antagonist L-822429 injected either systemically or locally into the LS reduced passive and facilitated active stress-coping strategies in the forced swim test. This effect seems to be mediated by enhanced intraseptal serotonergic transmission via serotonin (5-HT)1A receptors since NK1R blockade reversed the swim stress-induced decrease to an increase in extracellular 5-HT efflux, and furthermore the behavioral effects of L-822429 were blocked by intraseptal 5-HT1A receptor antagonism. A direct heterosynaptic regulation by NK1R on 5-HT release from serotonergic fibers was ruled out by immunocytochemistry at the light and electron microscopic level indicating involvement of GABAergic interneuron(s) in this interaction. Taken together, our data identify the LS as a critical brain area for the involvement of SP transmission in the modulation of stress responses and demonstrate that NK1R blockade can elicit a functionally significant facilitatory effect on 5-HT transmission, which does not necessarily involve the previously proposed interaction with neuronal firing at the cell body level of raphe neurons.

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Section: Effects Of Intraseptal and Systemic Nk1r Antagonist Administmentioning

confidence: 99%

Section: Effects Of Intraseptal and Systemic Nk1r Antagonist Administmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Ebner

Singewald

Whittle

et al. 2007

Neuropsychopharmacol

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“…Because NK1 receptors display considerable divergence between species, NK1R antagonists developed for activity at the human NK1R may possess limited efficacy in rat studies (Leffler et al, 2009). We therefore used L822429, a brain-penetrant NK1R antagonist with high affinity for the rat NK1R that produces anxiolytic-like effects after systemic administration (Ebner et al, 2004;Ebner et al, 2008;Singewald et al, 2008). We examined the effects of L822429 on heroin self-administration in short (ShA; 1 h per day) and long access (LgA; 12 h per day) rats.…”

Section: Introductionmentioning

confidence: 99%

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Barbier

Vendruscolo

Schlosburg

et al. 2012

Neuropsychopharmacol

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Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin selfadministration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxietylike behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward-and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

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“…All drugs were bath applied. SP was obtained from Bachem (Heidelberg, Germany), TTX from Biotrend (Cologne, Germany), and the NK1R agonist [Sar 9 ,Met(O 2 ) 11 ]-SP from Tocris (WiesbadenNordenstadt, Germany), and the NK1R antagonist L-822429 was synthesized in house as described previously (Singewald et al 2008). Drug effects were determined by measuring peak amplitudes of near-maximal responses under current-clamp or voltage-clamp conditions.…”

Section: Animalsmentioning

confidence: 99%

“…SP and NK1R display a widespread distribution in the brain (Cuello and Kanazawa 1978;Mantyh et al 1989), with high expression levels in the amygdala (Cassell and Gray 1989;Shigematsu et al 2008;Singewald et al 2008;Sreepathi and Ferraguti 2012). The amygdala is a key region of the brain involved in processing and propagating fear-and anxietyrelated signals.…”

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confidence: 99%

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

Sosulina

Strippel

Romo-Parra

et al. 2015

Journal of Neurophysiology

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HC. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation. J Neurophysiol 114: 2500 -2508, 2015. First published September 2, 2015; doi:10.1152/jn.00883.2014.-Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at Ϫ101.5 Ϯ 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K ϩ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar 9 ,Met(O 2 ) 11 ]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKC␦-negative neurons (80%) and in few PKC␦-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKC␦-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. substance P; central amygdala; neurokinin type 1 receptor; PKC␦

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Modulation of basal and stress‐induced amygdaloid substance P release by the potent and selective NK1 receptor antagonist L‐822429

Cited by 49 publications

References 95 publications

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

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